Electronic Supplementary Material (ESI) for Medicinal Chemistry Communications This journal is © The Royal Society of Chemistry 2013

Supporting Information

Mechanistic insight into inhibition of two-component system signaling

Samson Francis,a Kaelyn E. Wilke,a Douglas E. Browna and Erin E. Carlsona,b*

a Department of Chemistry, Indiana University, 800 E. Kirkwood Avenue, Bloomington, Indiana, USA. b Department of Molecular and Cellular Biochemistry, Indiana University, 212 S. Hawthorne Drive, Bloomington, Indiana, USA. Corresponding Author: [email protected]

Contents Supporting Information Figures and Tables………………………………………………………………..2 Docking-Based Virtual Screening ...... 34 General ...... 34 Docking of Compounds...... 34 In Vitro Activity Assays ...... 35 General Methods and Information ...... 35 Experimental Methods ...... 35 HK853 Construct (Thermotoga maritima) ...... 35 PCR Site-Directed Mutagenesis for Generation of HK853 D411A Construct ...... 35 Circular Dichroism (CD) Spectroscopy of HK853 Proteins ...... 37 Rescue ABPP analysis of NH125 (3), 48, 49, 50 and 51 ...... 39 Saturation Transfer Differential NMR Experiments ...... 40

Determination of Kd Using STD-NMR ...... 40 Measurement of STD Amplification Factors ...... 43 References ...... 43

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Electronic Supplementary Material (ESI) for Medicinal Chemistry Communications This journal is © The Royal Society of Chemistry 2013

Supporting Information Figures and Tables

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Electronic Supplementary Material (ESI) for Medicinal Chemistry Communications This journal is © The Royal Society of Chemistry 2013

Table S1. Rank and score of compounds reported to demonstrate TCS inhibitory activities and their corresponding Surflex score, rank, and documented biological data.

# Structure Receptor 1ID0 Receptor 1I58 Receptor 2C2A Receptor 3CGY

Surflex Rank Surflex Rank Surflex Rank Surflex Rank TCS Tested IC50 HK IC50 RR MIC Ref. Score Score Score Score (µM) (µM) 2.6341 1029 3.251 1030 3.5142 1040 3.0847 953 1 AlgR2 2 - - 1

3.0404 1009 3.518 1018 3.8778 1029 1.6857 1040 2 AlgR2 2 - - 1

5.2403 559 8.7544 79 9.2257 141 6.3868 126 3 AlgR1 0.4-0.6 - - 1 AlgR2

CheA NRII KinA 7.868 52 9.8076 23 8.7226 212 5.6508 278 4 AlgR1 0.4-0.6 - - 1 AlgR2 CheA NRII KinA 9.8154 6 8.2835 132 9.2701 143 6.8504 75 5 HpKA-DrrA - - - 2

4.4319 808 3.7157 1002 5.0129 984 2.6174 1005 6 HpKA-DrrA 30 30 1 2

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6.1823 311 6.2405 533 7.7782 412 5.3572 353 7 HpKA-DrrA 29.5 29.5 - 2

5.3822 522 6.9377 373 9.3379 128 5.6119 276 8 VicK 542.3 - 100 3

7.8251 58 7.6137 231 9.078 159 5.9994 192 9 VicK 562.4 - 50 3

6.0155 357 8.5172 101 10.0246 58 5.3371 359 10 VicK 502.6 - 100 3

6.0603 342 7.1185 334 8.4564 268 5.8769 214 11 VicK >1000 - 100 3

7.7916 61 7.3906 277 8.6092 234 5.7907 235 12 VicK 598.1 - >1000 3

5.2888 546 4.6756 896 7.8139 405 4.9899 460 13 VicK 32.60 - 0.28 3

5.3948 516 3.9942 978 6.3423 786 4.4055 630 14 YycG 48 - 50 4

5.2857 547 8.0385 167 10.4673 31 5.1475 414 YycG 29 - 25 4 15

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5.5479 478 6.6358 439 6.5453 733 5.3259 366 YycG 15 - 12.5 4 16

7.6617 73 7.7787 203 11.8361 4 6.8505 74 YycG 13.5 - 12.5 4 17

7.0096 157 7.7609 207 10.9232 16 7.8013 14 YycG 14 - 6.25 4 18

5.3834 521 4.8536 844 6.5453 733 4.3176 665 YycG >200 - 100 4 19

7.1043 134 8.9119 64 10.6944 21 5.863 220 YycG 6.5 - 0.2 4 20

6.2702 292 7.1734 324 4.793 1002 4.787 515 HpKA-DrrA 0.41 - - 5 21

7.0299 153 8.2833 133 8.9824 171 4.1039 737 YycG 76.5 - 25 6 22

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3.0818 1006 4.2318 953 6.3662 779 4.0584 750 KinA-Spo0F 3.8 3.8 1 7, 8 23

2.911 1017 1.7244 1045 4.4539 1019 3.8547 805 KinA-Spo0F 45 45 0.5 8 24

4.3917 823 4.9325 832 4.9996 986 4.3085 667 KinA-Spo0F 25 25 0.25-1 9 25

8.6015 23 9.6129 30 10.2441 46 8.0292 8 KinA-Spo0F 18 17 2 26 NRII -NRI

8.4203 28 9.6948 26 9.8122 75 7.329 41 KinA-Spo0F 20 20 1-8 10 27

7.1628 120 8.1661 150 8.7985 201 5.3119 371 KinA-Spo0F 14 14 2-16 10 28

7.3131 105 9.7372 24 10.1496 50 8.5535 4 KinA-Spo0F 500 500 >32 10 29

8.8116 17 11.9226 1 10.1188 51 8.0015 10 KinA-Spo0F 1.6 1.6 1-2 7, 10 30

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2.0797 1041 5.9444 605 7.6126 453 3.7753 824 KinA-NR 10 13 2 31 II 7

2.8973 1018 2.4744 1043 3.8343 1033 3.5477 871 KinA-NR 4 23 2 32 II 7

9.1179 15 11.8906 2 12.2995 2 7.9565 12 KinA-NR 13 37 1-2 33 II 7

7.1542 122 7.7735 206 7.1523 570 6.3414 135 KinA-NR - - 1-2 34 II 11

5.7593 419 6.5629 463 7.4925 479 6.5575 109 KinA-NR 1.6 1.6 2-4 35 II 11

9.675 8 8.4989 103 10.0395 57 5.4886 317 NR -NR 2.2 5.0 4.0 36 I II 12 KinA-Spo0F KinA- NRI-NRII Spo0F

6.1775 314 7.6961 218 10.9788 15 6.7903 80 HprK/P - - - 37 13

4.0165 896 5.0779 797 6.0328 845 3.5474 872 NR 20 1.6 0.78 38 II 14

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10.6889 2 9.8774 21 10.2665 43 6.2297 159 YycF-YycG 211-232 - 15.3 41 15

8.1599 37 7.6784 221 10.0723 54 5.9517 197 YycF-YycG 43.9 - 25 42 16

2.5472 1031 3.3949 1026 5.8565 876 5.0749 431 SF-EnvZc 70.17 70.17 12.5 43 11

5.5586 475 6.5012 479 9.15 147 4.2241 695 SF-EnvZc 10.18 10.18 12.5 44 11

6.5939 222 8.2712 136 10.0048 60 5.1254 418 SF-EnvZc 10.2 10.2 - 45 11

6.2265 301 6.1311 558 9.9799 63 4.8146 500 YycF-YycG - - 25-100 46 17

6.501 241 8.0366 168 8.331 295 5.7463 251 YycF-YycG - - 25-100 47 17

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Fig. S1 The fragment-guided docking approach in Surflex. A portion of the co-crystallized ligand (shown with the adenine moiety in the receptor PhoQ, PDB: 1ID0) is retained and utilized to guide the placement of compounds in the active site.

Fig. S2 The docked conformation of AMP-PNP in the active site of PhoQ superimposed with the adenine moiety (orange) of the co-crystallized structure. The computed RMSD between these two moieties was 0.108.

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Fig. S3 Predicted binding poses of selected TCS inhibitors in the nucleotide-binding region of HKs. Some portions of the protein have been cut away for clarity. (A) Compound 4 interacting with Asp449 in receptor 1I58. (B) The interaction of compound 15 with Asp411 in receptor 2C2A. (C) Asp415 interacting with inhibitor 20 in receptor 1ID0. (D) Salt-bridge interaction formed between inhibitor 30 and Asp416 of 3CGY.

Fig. S4 Cluster of guanidine-bearing compounds (26, 27, 30, 33) and their corresponding interactions with Asp416 of PhoQ (3CGY; E. coli).

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H Box ______Input_pdb_SEQRES_2C2A ------M E N V T E S K E L E R L K R I D ------R M K T E F I A N I S H E L R T P L T A UniRef90_A5IIT0_236_493 ------V E N V T E S K E L E R L K R I D ------R M K T E F I A N I S H E L R T P L T A UniRef90_B9KAB5_220_473 ------V E N I T A S K E L E R L K R I D ------R M K T E F V A N I S H E L R T P L T A UniRef90_UPI000210F96E_244_482 ------D V T N T K E L E R L K Q I D ------A L K T E F I A N V S H E L R T P L A A UniRef90_B7IDY9_224_462 ------N V T Y E I E L E K L K Q L D ------K M K T E F V A N I S H E L R T P L T A UniRef90_A6LN40_223_461 ------N V T Y E M E L E K L K Q L D ------K I K T E F V A N I S H E L R T P L S A UniRef90_A8F6Z9_244_486 ------D V T N T K E L E K L R A A D ------R L K T D F I A T V S H E L R T P L T A UniRef90_A7HK36_224_466 ------I R N I T S E K E V Q K L K E L D ------K I K T N F I A N I S H E L R T P L A A UniRef90_D5WTD2_380_614 ------I H D V T E R R R L E ------Q V R K E F V T N V S H E L K T P V T A UniRef90_Q67RF9_205_438 ------R D I T R S R Q L E ------Q M R T E F V A N V T H E L R T P L T S UniRef90_B3E3A4_350_579 ------L K R V E ------T M R R D F V A N V S H E L R T P V A V UniRef90_C1P968_353_593 ------L H D V T E T R R L E ------Q I R S E F V A N V S H E L K T P V T S UniRef90_UPI000210FB4E_174_410 ------M H D I T K E H E L N ------E M R K E F V S N V S H E L R T P L T S UniRef90_D7AHN4_358_582 ------L K R L E ------V V R R D F V A N V S H E L R T P V T V UniRef90_D5X969_353_585 ------D I T E I R E L E ------K M R S E F V A N V S H E L R T P L T S UniRef90_D8PBL4_363_603 ------D I T E L R R L E ------K I R K D F V A N V S H E L R T P L T S UniRef90_D7UVZ9_356_591 ------D I T Q I K H L E ------N V R T E F V T N V S H E L K T P V T A UniRef90_C5D651_348_580 ------D I T E L K K L E ------Q M R K D F V A N V S H E L K T P I T S UniRef90_F4BLP5_336_567 ------D I T E I R R L E ------K V R T D F V T N A S H E L K T P V T A UniRef90_Q3MGM2_1112_1344 ------R D I T E R K Q I E ------R M K D E F V S V V S H E L R T P L T S UniRef90_B8G4S5_316_540 ------Q N T F I S V I S H E L R T P V S I UniRef90_E0FRK4_227_461 ------N K M A E E L G Q L E ------E M K N E F I S N I S H E L K T P L T S UniRef90_B1ZT44_154_390 ------D V T R L Q Q L E ------A I R Q D F V A N V S H E L R T P L S L UniRef90_C9RTX6_347_579 ------D I T E L K R L E ------Q I R K D F V A N V S H E L K T P V T S UniRef90_A4XMJ6_338_561 ------K L D ------S M R K Q F V A N V S H E L R T P I T T UniRef90_UPI00018511C5_286_519 ------D I T E L K K L E ------Q M R K D F V A N V S H E L K T P I T S UniRef90_A5ILS8_180_410 ------R K L D ------E M R R E F I A T V S H E L R T P L T S UniRef90_B9K7H6_180_412 ------R K L D ------E M R R E F I A T V S H E L R T P L T S UniRef90_F2I7J7_353_596 ------V V L A Y D I T E I R R L E ------K V R S D F I A N A S H E L K T P V T A UniRef90_B5YHW7_385_611 ------N ------R A K S E F L A N M S H E L R T P L N S UniRef90_C0A490_167_399 ------I T R Q K R L E ------A V R K E F V A N V S H E L R T P L S V UniRef90_D6XVE0_357_597 ------M R D M T E E R L H D ------K L R K D F I A N V S H E L R T P I S M UniRef90_A6CR52_338_570 ------D I T E L K K L E ------Q M R K D F V A N V S H E L R T P I T S UniRef90_F5SLG1_353_585 ------E I T A I R R L E ------K M R T E F V A N V S H E L K T P V T S UniRef90_A4FWN1_406_639 ------L K E L D ------N L K S E L I A I V S H E L R T P L T S UniRef90_D3URW5_355_589 ------D I T Q I R H L E ------N V R S E F V T N V S H E L K T P V T A UniRef90_E8R548_187_428 ------F H N I T E L R R L E ------R M R Q D F V A N V S H E L K T P L A S UniRef90_C9RD18_197_417 ------F V A N V S H E L R T P L T A UniRef90_C1PEW1_349_587 ------V T I I R D M T E E R K L D ------K L R D D F I A N V S H E L R T P V A M UniRef90_Q1DCL6_267_509 ------V Y T G R A L Y R E A Q L S ------R M K T D F V S L V S H E L R T P L T S UniRef90_A8F5W9_184_414 ------L N ------E M R R E F V S N V S H E L R T P L T S UniRef90_Q2RFL3_239_485 ------R D I T D I R R L E ------Q M R T E F V A N V S H E L R T P L T S UniRef90_D1JAG2_243_467 ------E R L K E L D ------R L K S D F V S M V S H E L K T P L T A UniRef90_E5WJB7_351_584 ------D I T E L K K L E ------Q M R K D F V A N V S H E L K T P I T S UniRef90_F6CIV3_222_456 ------L R D I T E R K K L E ------Q M R T E F V A N V S H E L R T P L T S UniRef90_F6DKA0_218_449 ------R D V T Q R R K L E ------K M R T E F V A N V S H E L R T P L T S UniRef90_E3Z246_18_252 ------D I T Q I R H L E ------N V R S E F V T N V S H E L K T P V T A UniRef90_B5YHI6_153_383 ------D I T R L K Q L E ------N V R R D F V A N V S H E L K T P V T A UniRef90_A9GF59_268_496 ------L R R L E ------T I R T D F V A N V S H E L R T P V T A UniRef90_E8WRA5_348_584 ------D I S A M K K A D ------Q I R R D F V A N V S H E L R T P V T V UniRef90_Q097K6_265_506 ------V Y T G R V L Y R E A K L S ------R L K T D F V S L V S H E L R T P L T S UniRef90_E1KHP7_365_592 ------Q K L D ------N M R R E F V A N V S H E L R T P L T S UniRef90_A9AVU3_644_869 ------D ------R M K T E F V A T A S H E L R T P L T S UniRef90_A6UWZ1_410_640 ------L K K L D ------K F K S E I I S I V S H E L R T P L T S UniRef90_D4Y401_348_580 ------D I T E L K K L E ------Q M R K D F V A N V S H E L K T P I T S UniRef90_D7ATL0_341_566 ------K L D ------T M R K E F V A N V S H E L R T P I A T UniRef90_Q1PXZ9_292_526 ------K A V S A L K R A N ------R M K S E F L A N M S H E L R T P L N A UniRef90_E7M6U2_368_603 ------V R R L E ------R I R S E F V A N V S H E L K T P V A A UniRef90_D7BCF8_586_818 ------I R D V T P Q K D A E ------R I K S E F I A A V S H E L R T P L A A UniRef90_D0MGH9_109_352 ------T L E K E I E E L K R M E ------N Y R R E F L G N V S H E L K T P I F S UniRef90_UPI000212A698_523_767 ------E K L I Q A K E G A E L A S ------K T K S E F L A N M S H E L K T P L T A UniRef90_E1K386_410_648 ------Q A E E L E K S Y N E L K E L D ------K L K S D I V A I V S H E L R T P L T S UniRef90_B9M7U2_251_475 ------K E I E ------Q M K D E M I S A V S H E M R T P L T A UniRef90_Q3AAG9_206_440 ------F D D I T E E R K L E ------K M R S E F I A N V S H E L R T P L T S UniRef90_UPI0001E8932B_350_584 ------D I T E L K K L E ------Q M R K D F V A N V S H E L K T P I T S UniRef90_C4G960_243_473 ------L G R M Q S V E ------A S R Q E F V S N V S H E L K T P L T S UniRef90_C6J6K9_342_579 ------Q D V T E I R K L E ------R M R S E F V A N V S H E L K T P I A A UniRef90_A0YQV3_1128_1360 ------Q L E R A T ------R L K D E F M A N M S H E L R T P L Y S

Fig. S5 The complete multiple sequence alignment (MSA) of HK homologs retrieved from the UniProt database and aligned using the Consurf Protein database.18 Highly-conserved active site residues are outlined in red and indicated by a red arrow (Asn found in N Box region, Asp found in G1 box region, Leu found in G2 box).

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Electronic Supplementary Material (ESI) for Medicinal Chemistry Communications This journal is © The Royal Society of Chemistry 2013

UniRef90_E3PT03_185_421 ------I E D I T E R I K L E ------T I R S D F V A N V T H E L K T P L T S UniRef90_B7GGU1_348_587 ------D I T E L K K L E ------Q M R K D F V A N V S H E L K T P I T S UniRef90_Q39S62_358_588 ------L T R L E ------N I R R D F V A N V S H E L R T P V T V UniRef90_B8D0H3_363_592 ------L R R L E ------Q L R K E F V A N V S H E L K T P L T S UniRef90_F5L948_225_461 ------D I T Q L K K L E ------R I R Q D F V A N V S H E L K T P I T S UniRef90_E0NJE3_365_590 ------R L D ------V M R R E F V A N V S H E L K T P I T T UniRef90_A7II27_682_911 ------Q L R T L D ------E L K D D F V S S V T H E L R T P L T A UniRef90_B9DNB3_332_557 ------D I T S L K K L E ------N L R R E F V A N V S H E L K T P I T S UniRef90_A7HN49_181_412 ------K Q L D ------K L R R E F I S N V S H E L R T P L T S UniRef90_E6QIY0_358_593 ------R R L E ------R M K D E F V S T V S H E L R T P L T S UniRef90_F4L5H3_895_1123 ------E R L Q Q V D ------K L K D Q F L A N T S H E L R T P L Q G UniRef90_A9AUY3_448_692 ------I E D V T R E R E I D ------K M K N E F V S V V S H E L R T P L T S UniRef90_Q1IKU6_785_1018 ------Q D V T K R R E V D ------R M K N E F I S V V S H E L R T P L T S UniRef90_B5YD58_456_687 ------R D I S L A K E L D ------R M K S E F V A N V S H E L K T P L T A UniRef90_UPI00016BFB3D_364_592 ------M Q D V T S Q Q K L D ------Q M R K D F V A N V S H E L R T P L T T UniRef90_E8SIU9_335_566 ------D I T Q L K K L E ------N L R S E F V A N V S H E L K T P I T S UniRef90_B9E797_336_561 ------D I T Q L K I L E ------Q M R K D F V A N V S H E L K T P I T S UniRef90_Q8EPE4_222_453 ------D I T E L K K L E ------K M R K D F V A N V S H E L R T P I T S UniRef90_D5DL55_355_590 ------R D M S E E R K L D ------K S R K D F I A N V S H E L R T P I S M UniRef90_E0HX50_173_410 ------L R D I T K E K E V E ------A M R R D F V A N V S H E L R T P L T S UniRef90_B8DZU7_455_686 ------R D I S L A K E L D ------R M K S E F V A N V S H E L K T P L T A UniRef90_D6GSX7_369_596 ------E R L D ------H M R K E F V A N V S H E L K T P I T T UniRef90_D7CLL1_123_351 ------R K F D ------Q M R S E F V A N V S H E L R T P L T A UniRef90_Q6LXP6_406_633 ------L K E L D ------K L K S E L I A V V S H E L R T P L T S UniRef90_Q67LR3_257_496 ------R D I T K E T E L D ------R M K T E F I A T V S H E L R T P M T S UniRef90_A6LP23_177_414 ------L H D V T Q E R I L E ------N A R K E F I S N V S H E L R T P L T S UniRef90_B1HWE4_263_498 ------M H D I T E L V R L E ------Q I R K D F V A N V S H E L R T P I T S UniRef90_Q2B2H9_351_585 ------D I T E L K K L E ------Q M R K D F V A N V S H E L K T P I T S UniRef90_B8FA30_356_583 ------D M T Q V T K L E ------N M R R D F V A N V S H E I K T P I T A UniRef90_B5YJP0_360_619 ------R D I T Q E K E V D ------R L K T E F I T V V S H E L R T P L T S UniRef90_F0JJT0_240_468 ------R L R R E E ------R M R A D F V A M L S H E I R T P L T S UniRef90_E1KHE7_585_832 - I T E H K E I E S M L I E T N N K L K E L D ------Q A K T D F F S N V S H E L R T P L T I UniRef90_C9LCS1_237_475 ------N K M L K K M K V L D ------D S R Q E F V A N V S H E L K T P M T S UniRef90_B7IEX9_176_421 ------L H D V T Q E R V L E ------N V R K E F I S N V S H E L R T P L T S UniRef90_Q8TMU8_474_720 - I T E R K N Y E I E L F R A K Q D A E V A N ------R A K S A F L A N M S H E L R T P L N S UniRef90_Q71Y67_354_593 ------R D M T E E K Q L E ------K M K S D F V N N V S H E L R T P I S M UniRef90_D5DMV7_352_585 ------D I T E L K K L E ------Q V R R D F V A N V S H E L K T P I T S UniRef90_A5D189_222_456 ------L R D I T E R K I L Q ------E M R S E F V A N V S H E L R T P L T S UniRef90_C0Z7X8_357_585 ------I R R L E ------K M R S E F V A N V S H E L R T P I T S UniRef90_D4TMU3_804_1043 ------R D I T E R K Q V E ------K M K D E F V S V V S H E L R T P L T S UniRef90_Q0W6Q5_299_531 ------E R L K S L D ------R M K M E F F T L I S H E L R T P L T T UniRef90_B9E6M6_350_585 ------K K I D ------Q M K Q M F I A N V S H E L R T P I Q M UniRef90_UPI000212C3B1_361_596 ------V R R L E ------R M R S E F V A N V S H E L K T P I A A UniRef90_A6UPU7_401_631 ------E E L K E L D ------N L K S D L I A I V S H E L R T P L T S UniRef90_A5UQE0_447_687 ------S D V T R E R E A D ------R L K S E F L S I I S H E L R T P L T S UniRef90_A1HSJ7_400_654 D I T E H K Q L E V K L T E A L A A A E A A N ------Q A K D Q F L A A M S H E L R T P L N A UniRef90_F2JII5_342_577 ------Q D V T K Q Q K L D ------Q M R K E F V A N V S H E L R T P L T T UniRef90_Q8R6U6_339_575 ------M H D I T E Q H K L D ------Q M R K E F V A N V S H E L R T P L A T UniRef90_Q8PT37_279_503 ------N ------R S M S E F L A T M S H E L R T P L T A UniRef90_D8G5S6_939_1165 ------K Q I E ------R M K D E F I S I V S H E L R T P L T S UniRef90_A8FJB5_372_608 ------E K I D ------A E R R E F V A N V S H E L R T P L T T UniRef90_A5ITL6_318_551 ------M H D I T N L K Q L E ------N L R R E F V A N V S H E L K T P I T S UniRef90_F6B3A9_217_450 ------L R D I T E R R K L E ------R M R T E F V A N V S H E L R T P L T S UniRef90_D9QVY1_356_592 ------R D V T E L R R L E ------Q I R T E F V S N V S H E L R T P L T S UniRef90_A9AA11_406_633 ------L K E L D ------N L K S E L I A I V S H E L R T P L T S UniRef90_D5E8Z5_365_588 ------E Q A N ------R T K S E F L A N M S H E L R T P L N S UniRef90_D2QCT5_672_903 ------E R L K Q S D ------E Q K D D F V S T V T H E I R T P L T S UniRef90_A3DHV5_362_596 ------L H D I T E Q Q K L E ------N M R K E F V A N V S H E L R T P L T S UniRef90_B0ADS6_194_431 ------I E D I T E L V K L E ------N M R K D F V A N V S H E L K T P L T S UniRef90_E7RC70_372_606 ------E K I D ------I E R R E F V A N V S H E L R T P L T T UniRef90_A0B593_141_369 ------L K E L D ------S I K S E F V S M V S H E L R T P L T V UniRef90_D4IVS0_239_469 ------I K K L Q A I D ------Q S R Q E F V S N V S H E L K T P L T S UniRef90_B1YMQ3_615_835 ------D ------R M K E E F V S T V S H E L R T P L S S UniRef90_C1F3B6_554_791 ------Q D I T E R Q R L D ------R M K D E F I S T V S H E L R T P L T S UniRef90_E7RJV0_231_462 ------Q D I T E L K K L E ------Q I R K D F V A N V S H E L R T P V T S UniRef90_D3UPQ2_354_596 ------R D M T E E K Q L E ------K M K S D F V N N V S H E L R T P I S M UniRef90_E0RD24_357_594 ------Q D I T A I R R L E ------N M R S E F V A N V S H E L K T P I A A UniRef90_F4LRR4_346_580 ------R D I T D L R K L E ------K V R T E F V A N I S H E L K T P L T S UniRef90_Q7NDS1_97_331 ------Q E L D ------Q A Q T D F V S T V S H E L R T P L T S UniRef90_Q647M8_182_410 ------L E E V T ------R M K T D F L S I T S H E L R T P L T P UniRef90_B8G6G1_479_712 ------D ------R L K D E F I G I V S H E L R T P L T S UniRef90_B7GKK3_359_585 ------R R L D ------K L R K D F I A N V S H E L R T P I A M UniRef90_C1DVW6_110_330 ------Q A K K D F V S N V S H E L K T P I S V UniRef90_C4L472_342_574 ------D I T E L K R L E ------K M R K D F V A N V S H E L K T P L T S UniRef90_D7GPR0_250_485 ------T I N K T L E K L K A V D ------Q S R Q E F V S N V S H E L K T P I T S UniRef90_B4S8R4_490_736 ------F R D I T E Q K K S E R L I K E N I R L K N D F I A N V S H E L R S P L F S UniRef90_A5GAH6_406_635 ------D I T E R K E M E ------Q M K D E M I S A V S H E M R T P L T A UniRef90_C6WZH9_504_741 ------V G T S T D I D D M K R Q E ------Q Q K D D F I K M A S H E L K T P V T T UniRef90_B0TGE0_245_473 ------V R R L E ------Q M R T E F V A N V S H E L R T P L T S UniRef90_D5E978_387_612 ------V K ------T T K T E F I A T M S H E L R T P L N A UniRef90_F5LRU7_361_595 ------M R R L E ------R M R S E F V A N V S H E L K T P I A A UniRef90_Q4A159_364_598 ------L H D V T E Q Q Q V E ------R E R R E F V A N V S H E L R T P L T S

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Electronic Supplementary Material (ESI) for Medicinal Chemistry Communications This journal is © The Royal Society of Chemistry 2013

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Input_pdb_SEQRES_2C2A I K A Y A E T I Y N S L ------G E L D L S T L K E F L E V I I D Q S N H L E N UniRef90_A5IIT0_236_493 I K A Y A E T I Y N T L ------E E L D L G T L K E F L E V I M D Q S S H L E N UniRef90_B9KAB5_220_473 I K A Y T E T M Y N S L ------E E L D T D T L K E F L E V V L D Q S N H L E N UniRef90_UPI000210F96E_244_482 I R A Y V E T I L N S L ------D E L N K T M L K D F M K T V F D E T L H L E N UniRef90_B7IDY9_224_462 I K A Y T E T L L N M E ------V D R E S Q R E F L E T V Y E Q S E R L E S UniRef90_A6LN40_223_461 V K A Y T E T L L N M E ------I D P E S Q K E F L S I I Y E Q S E R L E S UniRef90_A8F6Z9_244_486 I K A Y T E T I L A D P ------E S M D K D T L T G F L Q I V Y K E S L H L E S UniRef90_A7HK36_224_466 I K A Y V E T M L N M P ------M S Q E E I H E F L D V V Y S Q S I R L E E UniRef90_D5WTD2_380_614 I C G L A E T V V E E D ------L A - - P E E R R H F L E L I H R E A R R L E Q UniRef90_Q67RF9_205_438 I Q G F A E T L L E G A ------L D - E P E T A R H F V E I M L R E S R H L G A UniRef90_B3E3A4_350_579 I K G Y G E T L L D G A ------L E E S P E R S R R F V E I I V S H A E R L T N UniRef90_C1P968_353_593 V K G F A E T L L D G A ------M Y - D E A T L R E F L K I I Y D E S D R L H R UniRef90_UPI000210FB4E_174_410 I H G Y A E T L L N D P ------D I - D P E T R Q R F L S I I E N E A A R M T R UniRef90_D7AHN4_358_582 I K G Y A E A L A G G L ------V E E D P E R A G R F L E I I C S H S E R L A D UniRef90_D5X969_353_585 I K G F V E T L L D G A ------M E - D R E V A R R F L E I I N V E T N R L S R UniRef90_D8PBL4_363_603 I K G Y V E A L L D G G ------K D - E P A T A T A F L E I I M R Q S N R L N L UniRef90_D7UVZ9_356_591 L K G F A E T L L D G A ------M Y - D E A L L K K F L G I M K D E S D R L H R UniRef90_C5D651_348_580 I K G F A E T L L D G A ------M K - D E Q T L E Y F L S I I W K E S E R L Q T UniRef90_F4BLP5_336_567 L K G F S E T L L D G A ------M E - D K E V L K Q F L E I M L A E S S R L D F UniRef90_Q3MGM2_1112_1344 I H G S L G M L A S G L ------L P A D S E Q G R R L L E I A T D S T E R L V R UniRef90_B8G4S5_316_540 I K G F A E T M L R P D ------G Q F T V E Q Y R E A L Q V I G E E A D R L A R UniRef90_E0FRK4_227_461 I K G F A I T A M D L V ------E K N S E L Y E Y L N I I D E E T D R L S R UniRef90_B1ZT44_154_390 I K S A A E T L L D G G ------K N - D P A V N A R F L E I I D K H A N R L S L UniRef90_C9RTX6_347_579 I K G F A E T L L D G A ------M K - D E A A L E H F L T I I L K E S E R L Q T UniRef90_A4XMJ6_338_561 I K T Y S E T L L D ------V D - N E E T K K Q F L S V I I K E C D R M T R UniRef90_UPI00018511C5_286_519 I K G F S E T L L D G A ------L E - D R D T L E Y F L N I M L T E S D R L Q S UniRef90_A5ILS8_180_410 I H G Y A E T L L E D D ------L E - D K E L V K R F L K I I E E E S A R M T R UniRef90_B9K7H6_180_412 I H G Y A E T L L E D D ------L E - N K E L V K R F L K I I E E E S A R M T H UniRef90_F2I7J7_353_596 L K G F T E T L L D G A ------L E - D E D T A R E F V E I M N R E A N R L G F UniRef90_B5YHW7_385_611 I I G F T E V L Q D Q L ------F G T L N E K Q L E Y L K D I H D S A K H L L N UniRef90_C0A490_167_399 I K G Y A E T L I D G G ------P D M P P A Q R D R F L H I I R R H T D R L N T UniRef90_D6XVE0_357_597 L Q G Y S E A I I D D V ------A G - S D E E K K E L A Q I I Y D E S L R M G R UniRef90_A6CR52_338_570 I K G F S E T L L D G A ------M N - D K E T L E M F L N I I L R E S D R L Q S UniRef90_F5SLG1_353_585 L R G F A E T L L D G A ------A E - D P D M R K E F L E I I Q A E S L R L E R UniRef90_A4FWN1_406_639 I K G Y V E L V L D G T ------M G A I N D S Q R K C L Q V A D D N I V R L R R UniRef90_D3URW5_355_589 L K G F A E T L L D G A ------M Y - D E A L L K K F L T I I K E E S D R L H R UniRef90_E8R548_187_428 I R A Y A D S L L D W A ------L E - D P E I T R R F V S Q I D E Q A E R L D V UniRef90_C9RD18_197_417 I K G F V E A L E D G A ------L E - D R E T A Q E F L Q I I A S E T E R L I H UniRef90_C1PEW1_349_587 L Q G Y S E A I I D D I ------A A - S E E E K K E F A K I I Y D E T L R I G R UniRef90_Q1DCL6_267_509 I R M F I E T L A L G R ------L K - D P A Q T Q E V L T L L M R E T E R L S I UniRef90_A8F5W9_184_414 I H G Y A E T L L N D P ------D M - D A E T R D R F L K I I E N E S A R M S R UniRef90_Q2RFL3_239_485 I R G F V E T L L E G A ------L E - D P E V S R R F L G I I N H E A Q R L Q Q UniRef90_D1JAG2_243_467 M R T S A Q V L E A A G ------I A T E T K R E M L D I I L R N I D R Q T N UniRef90_E5WJB7_351_584 I K G F S E T L L D G A ------M E - D K Q A L N D F L S I I L K E S D R L Q S UniRef90_F6CIV3_222_456 I K G F L E T L L D G A ------M N - D P K T S R Q F L E I M S Q E T E R L T R UniRef90_F6DKA0_218_449 I N G F M E T L L D G A ------I D - D P V I A R R F L E I M N T E S N R L S R UniRef90_E3Z246_18_252 L K G F A E T L L D G A ------M Y - D E M L L K K F L T I I K E E S D R L H R UniRef90_B5YHI6_153_383 I K G Y A E T L L D G A ------I N - D K E N S K K F I E I I K N Q A D R L N A UniRef90_A9GF59_268_496 I S T A A E T L Q L G A ------L K - D P H E A A E F V D V I D R H A K R L R H UniRef90_E8WRA5_348_584 I K G Y A E T L L S G D ------L A D D P G R R D R F L G I I Q N H A D R L S D UniRef90_Q097K6_265_506 I R M F I E T L A L G R ------L K - D P A Q T Q E V L Q L L S R E T E R L S A UniRef90_E1KHP7_365_592 I K S Y S E T L M D G A ------L E - D K E T A Y R F L N V I N S E A D R M T R UniRef90_A9AVU3_644_869 I S G Y I D L L M L N T ------L G P L T E Q Q R Q F L S V V K N N I E R L N A UniRef90_A6UWZ1_410_640 I K G Y V E L V L D G T ------M G T I N E S Q K R C L E I A N E N I D R L K R UniRef90_D4Y401_348_580 I K G F A E T L L D G A ------M K - D E R T L E H F L S I I W K E S E R L Q T UniRef90_D7ATL0_341_566 I K S Y V E T L L Y S D ------V - - D A E Y S K K F L K I I D S E T D R M T R UniRef90_Q1PXZ9_292_526 I I G F A E V L K D K L ------C G E L N A E Q E D F V K D I H S S G R H L L Q UniRef90_E7M6U2_368_603 V K G F A E T L M A G A ------L E - D K E M A R S F L Q I I Y D E S D R L N R UniRef90_D7BCF8_586_818 I M G F A E L L T S G E ------I P L E E G Q E F L R I I Y D N G R R L K N UniRef90_D0MGH9_109_352 I R G F T E T L L E A D ------P G - D E A T R R A F L E K I L R N A D R L A N UniRef90_UPI000212A698_523_767 I I G F S E L L N T R M ------F G E L N E K Q L G F V E Y I I K N G N H L L E UniRef90_E1K386_410_648 I K G Y V E L V L D G T ------M G A I T E S Q K K C L E I A N K N I D R L K R UniRef90_B9M7U2_251_475 M L G F T E Y L L E N E ------V D P S Q L K N Y L N T I Y K E T A R L K E UniRef90_Q3AAG9_206_440 I K G F L E T L L D G A ------L E - D K T I A K H F L Q I M N S E T E R L T R UniRef90_UPI0001E8932B_350_584 I K G F S E T L L D G A ------M N - D K D T L E Y F L S I I L K E S D R L Q S UniRef90_C4G960_243_473 M K V L A D S I N S M E ------G A - P L E L Y Q E F M Q D M S H E I D R E T K UniRef90_C6J6K9_342_579 V K G F A E T L L A G G ------V K - D E E T T R S F L Q I I Y D E G D R L N R UniRef90_A0YQV3_1128_1360 I L G L S E V L Q Q E V ------Y G V L N A E Q L R S L S T I E Q S G Q H L L E

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Electronic Supplementary Material (ESI) for Medicinal Chemistry Communications This journal is © The Royal Society of Chemistry 2013

UniRef90_E3PT03_185_421 I N G F V E T L K S N A ------G I - N K A M R T K F L D I I E V E S N R L Q R UniRef90_B7GGU1_348_587 I K G F A E T L L D G A ------M H - D A Q T L E Y F L T I I L K E S E R L Q H UniRef90_Q39S62_358_588 I K G Y A E A L I D G A ------M E T D P E R A R K F V G I I L S H S E R L A A UniRef90_B8D0H3_363_592 I I G Y I D T I I D N D ------I K - D D T T I K R F L S I I K D E A D R L Y L UniRef90_F5L948_225_461 I K G F A E T L L D G A ------M Y - K E E H L K H F L S I I H K E A E R L H R UniRef90_E0NJE3_365_590 I G S Y T E T M L D V D ------M - - D L D S I R N F L R V I D R E N N R M A R UniRef90_A7II27_682_911 I R A L S E L M L D A P ------D M E E A Q R Q E F L A I I V G E S E R L G R UniRef90_B9DNB3_332_557 I K G F A E T L I D G A ------K N - D E N S L D E F L N I I L K E S N R I E S UniRef90_A7HN49_181_412 I H G Y A E A L L D D D ------L S - N K E L V R K F L G V I E S E S A R M T R UniRef90_E6QIY0_358_593 L R A S L G L I A S G A ------L E K R P E K Q K Q M I E V A L A N S D R L I R UniRef90_F4L5H3_895_1123 I I G L S E A L L E D E ------L D - - - P E R K A N L T M V V S S G K R L N S UniRef90_A9AUY3_448_692 I L G Y T E L L L A R E ------F K P V E R Q E F V Q T V Y D Q A N Q L S K UniRef90_Q1IKU6_785_1018 I R G S L G L L A G G A ------L R K D P E K A D R M L D I A L K N T E R L V R UniRef90_B5YD58_456_687 I K G Y S E L L I K M N ------L P P E K V R N Y Y Q I I Y K E S E R L T Q UniRef90_UPI00016BFB3D_364_592 I K T Y T E T L I S G A ------I D - E K E T A L D F L S V M E K E T D R M T T UniRef90_E8SIU9_335_566 M K G F T E T L I D G A ------K N - D E A S L D L F L N I I L K E S N R I Q S UniRef90_B9E797_336_561 I K G F T E T L L D G A ------K E - D K D T L E M F L D I I L K E S N R I Q V UniRef90_Q8EPE4_222_453 I R G F A E T L L D N N ------I T - D P A T - K E F M E I I Y K E S H R L Q L UniRef90_D5DL55_355_590 L Q G Y S E A I I D D I ------A S - T D E E K K E I A Q V I Y D E S L R M G R UniRef90_E0HX50_173_410 I H G Y A E T L A E D D ------L E - D K E T V Y R F L S I I E N E S A R M T R UniRef90_B8DZU7_455_686 I K G Y S E L L M K M N ------L P P E R V R N Y Y Q I I Y K E S E R L T Q UniRef90_D6GSX7_369_596 I R T Y S E T L L D G A ------L K - D P A I A K K F M E V I V K E S D R M T S UniRef90_D7CLL1_123_351 I K G F V E T L L D G A ------L E - D K L I C R R F L T I I E G E N N R L T R UniRef90_Q6LXP6_406_633 I K G Y V E L V L D G T ------M G A I N D S Q K K C L Q V A D D N I V R L R R UniRef90_Q67LR3_257_496 I K G A L G L V L G G A ------A G D L P P E A R E L L T I A R N N T D R L I R UniRef90_A6LP23_177_414 I H G Y A E A L L E D N ------L D - D K E L I R R F L T I I E S E A A R M T R UniRef90_B1HWE4_263_498 I K G F S E T L L D G A ------Y K - D E K M L I S F L E I I Y K E S N R L Q M UniRef90_Q2B2H9_351_585 I K G F S E T L L D G A ------M H - D Q A A L S A F L D I I L K E S D R L Q S UniRef90_B8FA30_356_583 I K G F V E T L L D G A ------L D - D K E N A K R F L E I I S R H T D R L K A UniRef90_B5YJP0_360_619 I L G F I E I I N K K F T E N I L P H L D M N N F R L S K A V N K I N K N F K I I L S E G E R I T S UniRef90_F0JJT0_240_468 V R E A V D L V G S G T ------F G E V N E K Q K R F L D I A G Q E S E R L S D UniRef90_E1KHE7_585_832 I L G Q V E A V L S G Q ------Y Y K N T L E P N S D I F K T I Q S N A L R L L K UniRef90_C9LCS1_237_475 I K V L A D S L A G Q E ------D V - P V E L Y K E F M Q D I A V E I D R E N K UniRef90_B7IEX9_176_421 I H G Y A E A L L E D D ------L E - D K E L I R K F L S I I E S E A A R M T R UniRef90_Q8TMU8_474_720 I I G F S D L L Y E K V ------Y G E L N L K Q T K A V G N I S N S G K H L L N UniRef90_Q71Y67_354_593 L Q G Y S E A I I D G V ------A Q - S D E E V R E F A Q I I Y D E S L R I G R UniRef90_D5DMV7_352_585 I K G F S E T L L D G A ------M E - D P Q L R Q Q F L S I I L T E S Q R M E S UniRef90_A5D189_222_456 I R G F A E T L L D G A ------L E - E P D T A R R F L E I I N S E T E R L S R UniRef90_C0Z7X8_357_585 I K G F T E T L L E G A ------M Q - D E E T C R N F L Q I I S D E S E R L Y R UniRef90_D4TMU3_804_1043 I H G S L G M L T S G L ------L S T T S E Q G K R L L Q I A T D S T E R L V R UniRef90_Q0W6Q5_299_531 I K G Y A E L L K D G T ------L G P V N D E Q R D R L S R I D A S V D R L T G UniRef90_B9E6M6_350_585 L Q G Y T E A I L D G I ------V S - E K S D V D E F L N I I L D E S K R L N R UniRef90_UPI000212C3B1_361_596 V K G F A E T L L A G A ------L N - D K E T A R S F L Q I I F D E S E R L N R UniRef90_A6UPU7_401_631 I K G Y V E L V L D G T ------M G T I N E S Q R K C L Q V A D D N I I R L R R UniRef90_A5UQE0_447_687 I M G Y T E L L L A R E ------F S P A E R R E F V Q T V Y N E A N H L Y Q UniRef90_A1HSJ7_400_654 I M G F S E V L L D Q H ------F G P L N D K Q Q V Y V N D I L D S A R H L L E UniRef90_F2JII5_342_577 V K S Y T E T L L D G A ------I D - E K E T A M H F L G V M E K E A D R M T A UniRef90_Q8R6U6_339_575 I K S Y V E T L L Y N D ------V - - D T E Y S K K F L R I I E T E T D R M T R UniRef90_Q8PT37_279_503 I I G F S E L M L G G S ------T G E F D E L N K K F L G N I S T S G K H L L S UniRef90_D8G5S6_939_1165 I H G S L G M L A S G L ------L K A D S E E G K R M L Y I A V D S T D R L V R UniRef90_A8FJB5_372_608 M R S Y L E A L A E G A ------I G - D K E L A P R F L S V T Q N E T E R M I R UniRef90_A5ITL6_318_551 I K G F A E T L I D G A ------K N - D A E S L D M F L N I I L K E S N R I E S UniRef90_F6B3A9_217_450 I N G F L E T L L D G A ------I E - D P K T A R H F L E I M N A E T K R L A N UniRef90_D9QVY1_356_592 I K G Y V E T L L D E R ------D C - E P G V R E R F L Q V I K D E T D R L E R UniRef90_A9AA11_406_633 I K G Y V E L V L D G T ------M G A I N D S Q K K C L Q V A D D N I V R L R R UniRef90_D5E8Z5_365_588 I I G Y S Q I L N Q N P ------S G N L D E K E L K Y S H N I L N S G E H L L E UniRef90_D2QCT5_672_903 I R A L S E I L H D Q A ------D M D E S M R Q E F L S R V I R E T E R L S R UniRef90_A3DHV5_362_596 I K S Y A E T L L D G A ------L E - D R E L A G K F L S V I N S E A D R M T R UniRef90_B0ADS6_194_431 I T G F V E T L K I N D ------D I - D K N T R N H F L D I I E K E S N R L K G UniRef90_E7RC70_372_606 M R S Y L E A L A D G A ------W Q - D P D L A P N F L N V T Q T E T E R M I R UniRef90_A0B593_141_369 I N S Y I E M F E D G M ------L G D L T D V Q K E K L Q L I R S Q T D T M I Q UniRef90_D4IVS0_239_469 M K V L A D S L N G S E ------D V - P I E M Y K E F M V D I G D E I D R E T K UniRef90_B1YMQ3_615_835 I Y G F T E L M L N R E ------I D P P K Q R K Y L T T I H S E T G R L T T UniRef90_C1F3B6_554_791 L R A A L G L I A G G A ------L Q R R P E K V Q Q M F D V A I G N C D R L V R UniRef90_E7RJV0_231_462 I K G F S E T L L D G A ------Y K - D T E T L L S F L E I M H T E S N R L E M UniRef90_D3UPQ2_354_596 L Q G Y S E A I I D G V ------A Q - S D E E V R E F A Q I I Y D E S L R I G R UniRef90_E0RD24_357_594 V K G F A E T L L G G G ------V K - D E E T A R S F L Q I I Y D E S E R L N R UniRef90_F4LRR4_346_580 I A G F V E T L L D G A ------Y K - S Q D H C K Y F L G I I K Q E T D R M T R UniRef90_Q7NDS1_97_331 I K G F V D T L L R S G ------S Q L S E A Q H R R F L R I I K N Q A D R L T R UniRef90_Q647M8_182_410 M K S Q L Q M L Q E G Y ------M G K L D K K Q E K S I E V V L R N L T R L E N UniRef90_B8G6G1_479_712 I L G Y T E I L L N R Q ------D L D S E S Q R E F L L T V S N E A D R L H K UniRef90_B7GKK3_359_585 L Q G Y S E A I V D D I ------A A - T D E E K K E L A K V I Y D E S L R M G R UniRef90_C1DVW6_110_330 L K S A V E T I E E E K ------D P V M I K K F V N I A K K R I E Q M D H UniRef90_C4L472_342_574 I R G F S E T L L D G A ------K E - V P E L R D Q F L D I I Q K E A T R M Q M UniRef90_D7GPR0_250_485 I R V L A D S L M G M E ------D T - P K E L Y Q E F M H D I S D E I D R E S K UniRef90_B4S8R4_490_736 I L G F S S T L L K E R ------K E L D F E T T G E F L G I I H D E S K R L S S UniRef90_A5GAH6_406_635 M L G Y T E F M L D N E ------V P A D Q Q R E Y L R I T L H E S E K L N E UniRef90_C6WZH9_504_741 I K G Y V Q L L K R T R ------K D S D D K F L V N S L N T I E N Q V N N L S V UniRef90_B0TGE0_245_473 I K G F V E T L L D G A ------L D - D T K V A R R F L S I I N E E T Q R L Q R UniRef90_D5E978_387_612 I I G F S Q L L S S N R ------Y G N M N E K E L K Y S F S I L K G G K H L L N UniRef90_F5LRU7_361_595 V K G F S E T L L A G A ------L D - D K E T A R S F L Q I I F D E S E R L N R UniRef90_Q4A159_364_598 M N S Y I E A L E S G A ------W K - D G E L A P Q F L S V T R E E T E R M I R

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Electronic Supplementary Material (ESI) for Medicinal Chemistry Communications This journal is © The Royal Society of Chemistry 2013

Input_pdb_SEQRES_2C2A L L N E L L D F S R L E - R K S L Q I N R E K V D L C D L V E S A V N A I K E F A S S H N V N V L F UniRef90_A5IIT0_236_493 L L N E L L D F S R L E - R K S L Q I N R E K I D L C G L I E S A V N A I K E F A S S H N V N V L F UniRef90_B9KAB5_220_473 L L N E L L D F S R L E - R K A L Q I K K E K T N I C E L L E S A V G A I K E F A A S Q G V K V F L UniRef90_UPI000210F96E_244_482 L V N Q I L D F A K I E - Q K T L K L E K T W F D L V E L C Q E V I Q S M G E F A K S K Q V S L E Y UniRef90_B7IDY9_224_462 L L N D L L D F T L I E - S G T M E L E Y S E F D L C E L I K E V V E N L K Q L A E K Y K V K I N V UniRef90_A6LN40_223_461 L L N D L L D F T L I D - S G S M E L E Y S K F N I C N V V D D V L K K L L S F A Q K Q D V K L E K UniRef90_A8F6Z9_244_486 L L D E L L D F A K L E - Q K A M V L E K S K F D L T E L I M Q V I Q S M S E F A R S K K V K L Q C UniRef90_A7HK36_224_466 L L S D L L D F S Q L E - S H T M K I L K E S V N I C E I I E H S I E T L E N M A K E K D V T V E Y UniRef90_D5WTD2_380_614 L V R D L L D L S R L E - S H L T T L H R R P V D L A E M A R D V V Q D Y G Y A A E Q A G T D L Y L UniRef90_Q67RF9_205_438 L I D E L L D L S R V E - S G K F R M Q R R P T V P A E L I A A T A A R F A Q K A E R A G V Q L V T UniRef90_B3E3A4_350_579 L I N D I L T L S K L E - A R D A A L T L H P L D L C G T I R K A Q M L M E D H A R S K G I R I A A UniRef90_C1P968_353_593 L I S D I L D L S R I E - Q H R I L L K M E Q L N V V D V V A E T V Q T M R K R I E K K Q L E L V L UniRef90_UPI000210FB4E_174_410 L I N D L L D L E R L E - S G E A R F E F Q P V D L C S V I K Y V L S I V E P L A V Q Y G V K V E Y UniRef90_D7AHN4_358_582 L I R D L L T L S Q L E - S G G L Q L E L T Q I H L D R A V S H A A G L L E Q K A A R K E I A I D I UniRef90_D5X969_353_585 L I N D I L S L S S I E - A K N K E I S R S P V N F N E I V E K V L P I L V P M A E E K N I T V E T UniRef90_D8PBL4_363_603 I L D D L L Q L S Q I E - S G Q V L F R R E P V D L R A L L E R T V A V I K P L A D K K H H T I E L UniRef90_D7UVZ9_356_591 L I L D I L A L S R I E - Q H A L P I N Q E V V D I Y Q T I T E A A Q T V T E S A K Q K N I D L V L UniRef90_C5D651_348_580 L V Q D L L D L S K I E - Q Q G F R L H L E T V D L A D L L R E I A V M F Q Q K S E E K G I D F Y L UniRef90_F4BLP5_336_567 L V N D I L E L S K L E - Q K Q V P M N M Q E V N L T E A V L S T F Q L V K Q T A D E K E M K L N L UniRef90_Q3MGM2_1112_1344 L I N D I L D I E R I E - S G R V K M E R E S C N L T D L I E S A V S I M R P L A N K A G V K L S V UniRef90_B8G4S5_316_540 Q I Q D L L D V S R I A - A G G L R L E Y S D V S L Q L L V K E V V R R F A A Q V G D R - I E F E I UniRef90_E0FRK4_227_461 L V D E L L D F S K I E - L N K I K L S F E E V E L D K L I E D T V A I L R P H A S N D G V N L I C UniRef90_B1ZT44_154_390 L I D D L L T L S K L D - A E R V E L D I R S V G L R A A V Q D A L D D A L T L A Q P R A I A L E N UniRef90_C9RTX6_347_579 L V E E L L D L S K I E - Q H G F Q L Q L E D V D I A Q V I A E A A A V F R Q K A A E K Q I D L H I UniRef90_A4XMJ6_338_561 L V S D L L Y L S R L D - S G E N I L N L E E V N L S E L V R F V C E K L K I H A K K K N Q T L S C UniRef90_UPI00018511C5_286_519 L I Q D L L D L S K L E - Q H G F K L D V S T F D L S R L L E E V V L M L K G K A E E K E I Q L Q F UniRef90_A5ILS8_180_410 L I N D L L D L E K M E - E S E V N F E M K D V D L C E V I E Y V Y K I I Q P I A E E N E V D L V V UniRef90_B9K7H6_180_412 L I N D L L D L E K M E - E S S V E F E M K E L D L C E V V D Y V Y R I V Q P I A E E N E V E L E I UniRef90_F2I7J7_353_596 L I N D I L D L A K I E - Q D Q L G H R S E T V Q L N R V I A E V V H S L E I P A S E N R V E V H Y UniRef90_B5YHW7_385_611 L I N D I L D L S K I E - E G K T E L E L S E F R V S D V V N V S L I M F K E K A S K H G I K L D A UniRef90_C0A490_167_399 L L E D L L T L S R L E - S P N T G L R R E P G D L D R L V K T L L D E Y R T R P A A A R H T L Q L UniRef90_D6XVE0_357_597 L V N E L L D L A R I E - A G H I R L N L E P V N M T E F V E R I S R K F Q G V A D D N N V E L M G UniRef90_A6CR52_338_570 L I T D L L D L S K M E - K Q G F Q L N V H E T D M K E L L I E V I T I L E K K P E K K D I E L V L UniRef90_F5SLG1_353_585 L I A D L L D L S K I E - S R N M P L D I Q T I G I G E L L R S T A K T V E E Q M R K R K L S F R V UniRef90_A4FWN1_406_639 L I E S M L D L S K I E - R G E L E M Y R E K V N I C E I V G D V I Q Y L K P L A T E K N I K L N K UniRef90_D3URW5_355_589 L I M D I L A L S R I E - Q N P V T E N V G T V D V D D V I D Q S V R T I F E L A T E K N I Q V S A UniRef90_E8R548_187_428 L I H D L L S L A R I E - S G Q D L I T F R P L A L A P L V E R R V E S F R D R A Q S R N V S L S F UniRef90_C9RD18_197_417 L V E D L L K L S R L E - N R Q T F L R R Q E V N L N E L I H N I A L V W R R R A E E K G L A F E V UniRef90_C1PEW1_349_587 L V N E L L D L A R M E - A G H F S F R M E P V S F N S F I E R V T H K F N G I A K E K G I D L V C UniRef90_Q1DCL6_267_509 F V E R V L D W A R I E - G G R K V Y Q R E I V P V S E L V N A A V E A F R T Q R M E D G V D L T V UniRef90_A8F5W9_184_414 L I N D L L D L E R L E - S G E A R F D F Q K I D L C S V V K Y V V S I T E P L S I D Y D V K V E Y UniRef90_Q2RFL3_239_485 L I E D L L S L S R L E - S Q P K R Q D A G R A D L A A T L D R V L T T V N Q L A R E K G V A L E K UniRef90_D1JAG2_243_467 L V N D L L D L S R I E - S G R M K L K F E S V S L D S L I A D S I E S V K H A A S E K G I K L N V UniRef90_E5WJB7_351_584 L I Q D L L D L S K I E - K Q G F S L S I Q Q L D L T D V L E D V M A I M K G K A A E K E I V F K Y UniRef90_F6CIV3_222_456 L V D D L L D L S K I E - E R R V V H R W Q P V N L V D I I N R V A S L F R P Q A K E K A L T L S L UniRef90_F6DKA0_218_449 L V D D L L Q L S K L E - Y R K G N L N K Q P V N L T E V I R D T V E V F K N R A A E K N L S F T S UniRef90_E3Z246_18_252 L I M D I L A L S R I E - Q N P V A E N I E P V D V D E V I E Q S S R T I F E M A T E K N I Q V S V UniRef90_B5YHI6_153_383 L V E D L L T L S R I E - F G D I K I E K E N I V L D E L I S S V F Q I L K D K A Q K K G V L L Q K UniRef90_A9GF59_268_496 L V D D L L D L S K I E - A K N F R L A L S E L D I A P A I E H V T Q L L A E A A R R R R V T L T V UniRef90_E8WRA5_348_584 L V R D L L A L S E L E - S G E L A M Q P Q K V L I E D A V R Q A L L L L S P R A E E K G I V M E L UniRef90_Q097K6_265_506 L I E R V L D W A R L E - S G R K E Y Q R E P T A V A D V V D T A V A A F R A Q R L D G G V E L K V UniRef90_E1KHP7_365_592 L V K D L L Q L S R L E - N E Q M Q W N M Q P F C F E S L V R S S V E K I E L S A K E K R Q V I E C UniRef90_A9AVU3_644_869 I L N D L L D V S R I E - S G K V R L Q R K P I N L D E L I Q S T V M S I H Q Q W S G K Q I S L A L UniRef90_A6UWZ1_410_640 L I D N M L D L S K I E - R G E L K M D I S K V N L N D I V Q N V V H S L K P L A D G K N I K I I N UniRef90_D4Y401_348_580 L V Q D L L D L S K I E - Q Q E F Q L H M E T V D L T H L L H E I A I M F Q R K A E E K G I D F R M UniRef90_D7ATL0_341_566 L V K D L L L L S K M D - S E D N N L K F E Q K N L N D I V V E A I N R L S I E A Q K K N Q K L I V UniRef90_Q1PXZ9_292_526 M I N D I L D L S K I E - A G K M E L Q Y E S F L V S D A I E D V Y T I L K G L A K K K Q L Q L K T UniRef90_E7M6U2_368_603 L I G D I L E L S K I E - S K R I P L Q F S P V D V E S I V E N S I Q M M K A E A E K K H I T L E S UniRef90_D7BCF8_586_818 M V D N L L D S S R L E - A G R F E V Y K R P V Q L E E T L R G V A D S F T G V A Q L S Q V E F H R UniRef90_D0MGH9_109_352 L V R D L T E I S R L E - T G E L Q L Q P V P F E L P A L V R E V L E S M E P L A A T R Q V S L R C UniRef90_UPI000212A698_523_767 L I N N I L D L S K I E - A G R M Y L D R E I F C L S Y L I E E V L A T M Y P L A A K K K I D I E T UniRef90_E1K386_410_648 L I D N M L D L S K I E - H G E L E M H M E E I N L K E L V E N V V D T L K P L A D E K N I N I I Y UniRef90_B9M7U2_251_475 L I G N F L D L Q Q I N - A R M T T Y R M H P L D V C L L I K D A A G L F A L D Y D S G R L V V Q C UniRef90_Q3AAG9_206_440 L I D D L L S L S K I E - A K K V D F A P K P L M L Q E L I Q K M K L L F K S R L E E K E L S F I I UniRef90_UPI0001E8932B_350_584 L I E D L L D L S K I E - K Q G F R L N P Q Y L E I N E L L E E I F V I L E G K A R E K E I D L V L UniRef90_C4G960_243_473 I I N D L L S L V R M N - K T G I S M N I A S V N M N E L I E S I L H R V R P I A D R Q G V E L V L UniRef90_C6J6K9_342_579 L I G D L L E L S K I E - S K R V P L E Y A P V Q L S E L F D S L Y E V L L P A A E K K S I S M S H UniRef90_A0YQV3_1128_1360 L I N E I L D L S K I E - S G K M E L Q L S A V N L T Q L C Q S S L N F V K P Q A D Q K N I Q L Q F

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UniRef90_E3PT03_185_421 L I D D I L I L S F I E - G N K S H Y S N E P V N F A D T I N E C I N L V S E T I K D K N V T I D F UniRef90_B7GGU1_348_587 L I Q D L L D L S K I E - Q Q G F T L N I S V V D L H E V L K E V I V M L E A K A N D K Q I T L E Y UniRef90_Q39S62_358_588 L I G D L L T L S Q L E - A G S M N L E K T T V R P E Q V A K R A M E L L Q P K A A R K G I T I D C UniRef90_B8D0H3_363_592 L I K D L L D L S K L E - A K R G E V I L Q P G D L N K I V K K I Y L M L Q E Q A E S K D I D L K L UniRef90_F5L948_225_461 L V E D L L Q L S Q I E - Q R R F G L N W Q E V N L T E V L H N S L Q V V R A K A E V K N I E L I F UniRef90_E0NJE3_365_590 L V T D L L Q L S N M D - Y K E T K W N Y E A V D T Y D F L S T N I N S L D M L I K E K H H K V T L UniRef90_A7II27_682_911 L V N Q V L D M A K L E - S G H G E W H N A D V D L R R L V R D A V T A T T E L A R S R G A E I V F UniRef90_B9DNB3_332_557 L V E D L L D L S H I E - Q Q T - E I R T E R V D L S E V T Q T T V N T L Y A Y A Q R K A I E I D A UniRef90_A7HN49_181_412 L I N D L L D L E K L E - S G D A K F N F S D V N M C K V I E R V V T I L E P L A E D Y G V E L Y T UniRef90_E6QIY0_358_593 L V N D I L D F D R V E - K G G M A L N R E V I P V I D L L R R A A D V A H E A A T R A S V T F R F UniRef90_F4L5H3_895_1123 L V N D I L D F S K L K - N A D I E L D L R P I S L H S M A D V V L K N I S P L V A G K S I E L L N UniRef90_A9AUY3_448_692 M V D D L L N L S R L D - A G Q I K L N R W V V S L H Q I I R E I T K Q L N E T L S E K H - R L L I UniRef90_Q1IKU6_785_1018 L I N D I L D I E K I E - S G N I A L N V Q P L D A A D L I S Q A S A T M H A M A D A N K V R L E T UniRef90_B5YD58_456_687 L I N D L L E V S R I E - S G K I E L K K E M V E I R K V I K E R A T F F Q T Q T S K H T I V L Q F UniRef90_UPI00016BFB3D_364_592 L V H D L L E L S K I D - N K Q M Q L N I Q V M D I Y S L L L D T I R A Q A I Q A K C K H H Q I K L UniRef90_E8SIU9_335_566 L V E D L L D L S K I E - Q N T - T L E K H L I D L S D V A K S S F S V I Q P L A N E K S I Q L I D UniRef90_B9E797_336_561 L V S E L L E L S K I E - Q A N - H F N M V K V N L P Q K V F N S V E V V Y P L A E K K N I N F N L UniRef90_Q8EPE4_222_453 L I E D L L A L S R L E - R E D F R L L I D N Y D V R Q M V E E I L P Q L H Q K A E N K N L T F D L UniRef90_D5DL55_355_590 L V N E L L D L A R M E - A G H V Q L H L E S V A M V E F T E R V L R K F Q G L A K E K H I K L S L UniRef90_E0HX50_173_410 L I N D L L D L E K L E - S G E A S F S K E D V E L G E V V N Y V M R I V E P L A S E K N V S I N V UniRef90_B8DZU7_455_686 L V N D L L E V S R I E - S G R I E L K K D M V E I R K I I K E R A T F F Q T R T S K H T I V L Q F UniRef90_D6GSX7_369_596 L I R D L L Q L S H I D - F K K E T W N F D Y T D I N T L I Q D S I D K M E L Y Y Q T K H Q T L V S UniRef90_D7CLL1_123_351 L I D D L L T L S A I E - S R E R K L T L K P V C L V T S I I Q V M N I L G P Q A R E K R L H L E L UniRef90_Q6LXP6_406_633 L I E S M L D L S K I E - R G E L E M Y R E K V N L R S I V C D V I E Y L K P L A T E K N I K L N K UniRef90_Q67LR3_257_496 L I N D I L D I S R I E - A G K M E I R R A P L S P A D V V R R A V E E M N A F A R Q R N I T L T T UniRef90_A6LP23_177_414 L I N D L L D L E K L E - S G N T Q F I F E K I N F T E I L E H V R N I I E P L T K D Y N V D V E F UniRef90_B1HWE4_263_498 L I Q D L L E L S K I E - Q H G F T V N I M P M G L Q D V L I R G A E L T A P R L D E K N M S F Q V UniRef90_Q2B2H9_351_585 L I Q D L L D L S K T E - Q Q G F R L S V Q E M D L S S L L G E C L A I L N G K A K D K A I D I E Y UniRef90_B8FA30_356_583 I V E D L L E L S R I E Q A G G R E L P L E R A S V K E A L E T A V Q V C E A R A I S E N I T V E M UniRef90_B5YJP0_360_619 L I N D V L D I S K L E - S G K A I W N F K E I S I Q G V I T D A Y K A L S S L F E Q K G I P C Y I UniRef90_F0JJT0_240_468 L L T R L L S V S R M E - A E E L H L N P E R V D V A G L V E S T V E R L V P T A R A A S V T L E S UniRef90_E1KHE7_585_832 L I N T L L D F S K I Q - A G K M T L N R Q P V N I N R F L S S Y I S A V K S S A S Q K N I N M I F UniRef90_C9LCS1_237_475 I I T D L L S L V K M D - K K A S E L N I E K V N I N E L M E N I L K R L K P I A D K K K V E L V L UniRef90_B7IEX9_176_421 L I N D L L D L E K L E - S G N T Q F V F E K I N F T E V L E H V R N I I E P L A K D Y Q V E V E F UniRef90_Q8TMU8_474_720 L I N E I L D L S K V E - A G S F E L H Y S T F W L A E V F A E V R D M I F P F A T S K G L K I E L UniRef90_Q71Y67_354_593 L V N D M L D L A R M E - A G F N Q M D N Q K L P L A P L L R K V I S N F D V L A K E N Y V E L G L UniRef90_D5DMV7_352_585 L I Q D L L D L S K V E - Q Q G F K L S I H S V D L N T L L Y E V T T V L S N R A T E K E I T L T L UniRef90_A5D189_222_456 L I D E L L N L S R L E - S H K W V P K R Q P V N M G E L I K R A V A I L Q P R A V E K N L A I K I UniRef90_C0Z7X8_357_585 M I R D I L D L S K I E - Q K R I P L H L G Q V H L Q D L I S S A V A I M H D Q A Q R K E L T I T L UniRef90_D4TMU3_804_1043 L I N D I L D I E R I E - S G K V K M E R E N C D L R D L I N S A I N I M Q A L A D K A G V S L S I UniRef90_Q0W6Q5_299_531 I V E S L S D L S G V A - S R Q Y A G E K I P V S L N E L I E E V V R G I D F L A D L K K L K I T L UniRef90_B9E6M6_350_585 L V N E L L N V A R I D - A G E Q V L N L E A T D I E E L I E R T I M N F K H V A E K H E T E L Q T UniRef90_UPI000212C3B1_361_596 L I G D I L E L S K I E - S K R I P L Q F S P V H L E P F I G N C V H V M N T E A K K K G I E L E L UniRef90_A6UPU7_401_631 L I E S M L D L S K I E - R G E L E M Y R E A M N V K D T V S D V I E Y L T P L A T E K N I K L K Q UniRef90_A5UQE0_447_687 I V E D L L G V T R L E - A G N V R L N Q W A V S L R Q I V S D L T A Q L N N Q I S G K H T M L - I UniRef90_A1HSJ7_400_654 I I N D V L D L A K L N - A G K T N F Y P E T V D I A K L L R Q T L G I I K D R A A A K N I A V E L UniRef90_F2JII5_342_577 L V Q D L L E L S R I D - N K Q I Q L E F V R L N L K P L L E E V L E A Q Y I H I I K H G H Q L E V UniRef90_Q8R6U6_339_575 L V K D L L L L S K M D - S E E N S L K L E P C D F N E I V K N V V N S L S I E A T K K G H N V I L UniRef90_Q8PT37_279_503 L I N S I L D L S K I E - A G K M E L Q S D Y F S L Q D I F S N T K N I L S P L A L K K N I S M D F UniRef90_D8G5S6_939_1165 L I N D I L D I E R I E - S G R V K M E K Q C C N V E D L I T E A V N V V Q A L A N K V E V T L S V UniRef90_A8FJB5_372_608 L V N D L L Q L S K F D - S K D Y Q F N R E W T N F I R F I S L V I D R F E - M T K E Q H V E F I R UniRef90_A5ITL6_318_551 L V T D L L D L S H I E - Q H T - E L D T D Y M N L S D L T R R I I D N M M T Q A N Q K N I S I H T UniRef90_F6B3A9_217_450 L I D D L L Q L S R L E - D R K T V L N K Q P V D L R D V I N G T I Q M F K A R A E E K G I K L F T UniRef90_D9QVY1_356_592 L I T D L L N L S Q L E - S A S D S F D Q E L V N L N Q V I E N V L T T V M P K A D N K G I D L K V UniRef90_A9AA11_406_633 L I E S M L D L S K I E - R G E L E M Y R E K V N L K G I V C D V I E Y L Q P I A T E K N I K L K K UniRef90_D5E8Z5_365_588 L I N S I L D I S K V E - A G K M E Y E P E R V N L P E T I D D I I G L V K P L A M K K S I D I R F UniRef90_D2QCT5_672_903 L I N Q V L D L E R Y D - S G R Y H L S T E R I S M V D L V A E A V E N V A Q L A R D K Q V T L E I UniRef90_A3DHV5_362_596 L V K D L L Q L S R L D - N N Q M K W D M Q K I S F E D L V R N C V E K V K F E S E E K N Q T L E C UniRef90_B0ADS6_194_431 L I E D I L L L S S I E - N G Q - D L S Y E K V K L F D V F K E V C E I T E Y I A S S K N I T I S Y UniRef90_E7RC70_372_606 L V N D L L K L S K M D - S S E T E L S K E M V E F N V F F N R I I D R F E - M S K S H K V N F M R UniRef90_A0B593_141_369 L V N D M L D I L R I G - S R R L R L K K E L S S M E E L I R S V I A S L S R L A A L K E H T I T F UniRef90_D4IVS0_239_469 I I N D L L S L V R M D - K S G A E L N V S A V N I N E L I E H I L K R L K P I A E K A G I E V V F UniRef90_B1YMQ3_615_835 L V N D F L D V Q R M E - S S E Q R Y Q M A T F D L V Q L A A E L I D F H D A S H T T H E L S F E A UniRef90_C1F3B6_554_791 L V N D I L D F E R L G - S G K M Q L Q Y V Q M P A R D L L Q R A V D L Q H S S A Q K A N I T L R V UniRef90_E7RJV0_231_462 L I N D L L D L S K V E - Q S G F R V N A Q P T N M E A V I K R A R E M I Q P K I D E K S I Q L K L UniRef90_D3UPQ2_354_596 L V N D M L D L A R M E - A G F N Q M D N Q K L P L A P L L E K V M A N F D V L A K E N F V E L G L UniRef90_E0RD24_357_594 L I G D I L E L S K I E - S K R S T L D C S P V H V S S F I E S L L E K L N N V A A K K R I T L H M UniRef90_F4LRR4_346_580 L I N E L L Y F S H I E - K N G T E I I K K P V D M I E V I M K A L S I L Q T A I N E K K H K V N L UniRef90_Q7NDS1_97_331 L V E D I L T V S R I Q - S G R L K N L P Q R L D L G E M I D R V F E N L A Q K Y A A Q R M R R E L UniRef90_Q647M8_182_410 L I G D I L D L S R I E - A G R I K L S F D S M N L N D A V K E A I K M Q E A F A K G K N I E I S A UniRef90_B8G6G1_479_712 M V K D L L D V S R L E - A G V V K L N R W A V G L W Q V I E E L T L Q L H T Q L V Q H K L L I D M UniRef90_B7GKK3_359_585 L V N D L L D L A R M E - A G H L M L H H E Q V P L K P Y V E R I I H K F Q A L A K E K G V H L L V UniRef90_C1DVW6_110_330 L I N D L L I L A R L E - S Q E D Q V K K E R Y D L H K Q I E E I F E D L K H L T E E K E I Q L I N UniRef90_C4L472_342_574 L V E D L L E L S R L E - R D D F Q M E L V S V D L N Q L V D E V C L L L S Q K A S K K S I Q L E A UniRef90_D7GPR0_250_485 I I D D L L T L V R M D - K A S S G L S C S Q V Q I N G L I E M V L K R L R P I A R K R N I E L I F UniRef90_B4S8R4_490_736 L I E D V L N V S R I D - S G K V A Y K K K I I D P A P V V I G A C E S L K M M A S E K S V E F S I UniRef90_A5GAH6_406_635 L I G N F L D L Q R L R - S R K E T V T W R P L P L Q P L L E E T V A L F T R V S E R H H I T L D C UniRef90_C6WZH9_504_741 L I G D L L D I S R M E - N G Y L L L N K H K F S L V E L V T E S I E D I K A S E Q S H E I N F E M UniRef90_B0TGE0_245_473 L I E D L L Q L S R I E - S Q L G R V V E G Q S Y L E P E I Q R V R N L L E P I A A D K R I A L Q V UniRef90_D5E978_387_612 L I N D I L D F S K I H - S N K M E L N I E T I N L K E I C D E I K T F I T P L A T K K G I T V E Y UniRef90_F5LRU7_361_595 L V G D I L E L S K I E - S K R I P L Q L S P T H L Q S I I Q K S L H M M E A E A D K K K I A L S M UniRef90_Q4A159_364_598 L V N D L L Q L S K M D - N E S E Q I T K E I V D F N M F I N K I I N R H E M S A - - K D T T F V R

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N Box ______ê Input_pdb_SEQRES_2C2A E S N V P - - - - C P V E A Y I D P T R I R Q V L L N L L N N G V K Y S K - - K D - A - - P D K Y - UniRef90_A5IIT0_236_493 E S N V P - - - - C P V E A Y V D P T R I R Q V L L N L L N N G V K Y S K - - K D - V - - P D K Y - UniRef90_B9KAB5_220_473 E K K V - - - - - P C F E A E V D P T R M K Q V L L N L L S N G V K Y S K - - K D - E - - P E K Y - UniRef90_UPI000210F96E_244_482 E G P D ------Q L I V F A D R M R L R Q V L M N L V S N G I K Y S N - - P E - N - - R Y K Y - UniRef90_B7IDY9_224_462 S C ------E S I S I S A D K R R I K Q A I H N L V D N S I K F S D - - K S - K - - E E R Y - UniRef90_A6LN40_223_461 E C ------E D V E I S A D K R R I F Q V I Y N L V D N A I K F N D - - R E - K - - P E R F - UniRef90_A8F6Z9_244_486 V K S K ------P I Y I V A D Q K R I R Q V L I N L I S N G I K Y S K - - E E - A - - S E K Y - UniRef90_A7HK36_224_466 N C ------S N L E I K C D R K R I E Q V I V N L L S N A I K F S D - - Q A - K - - E K R F - UniRef90_D5WTD2_380_614 D K E G ------D C R A E V D P D R V R Q V L S N L I D N A L K Y T P - - A G - G - - R - - - - UniRef90_Q67RF9_205_438 E A P D - - - - - G L P L I N G D P D R L V Q V L S N L V E N A I K Y T P - - A G - G - - R - - - - UniRef90_B3E3A4_350_579 E C P D - - - - - G M P K V L A D Q G Q L E Q V L L N L L D N A I K Y T P - - D G - G - - D - - - - UniRef90_C1P968_353_593 P Q K R ------H V M M E A D K D R L R Q I L L N L V T N A I A Y T P - - D K - G - - R - - - - UniRef90_UPI000210FB4E_174_410 S C Q ------D I V L E A D Q D R L I Q M L V N L V D N A V K Y T S L K E T - G E K Q - - - - UniRef90_D7AHN4_358_582 S A L A - - - - - G A P P V L A D P G R L E Q V L I N L M D N A L K Y T P - - P G - G - - T - - - - UniRef90_D5X969_353_585 D I H P - - - - - D L P V I M A N E D L I K Q V L I N L V D N A I K Y T P - - E N - G - - R - - - - UniRef90_D8PBL4_363_603 S L P D - - - - - E Y W V V E G D E E R L V Q V F I N L L E N A V K Y T P - - D Q - G - - R - - - - UniRef90_D7UVZ9_356_591 P H A A - - - - - K P L P I E T D N D K L K Q I I I N L V S N A V A Y T P - - E N - G - - T - - - - UniRef90_C5D651_348_580 H A P K ------S V Y M E G D A N R I K Q I F I N L I T N A L T Y T P - - K G - G - - K - - - - UniRef90_F4BLP5_336_567 I E E D ------T L F I T V D S S R L K Q I L A N L I N N A V V Y T Q - - D S - G - - E - - - - UniRef90_Q3MGM2_1112_1344 S H ------P S I Q L W V D P D R I V Q T L T N L L S N A I K F S T - - A E - K - - T - - - - UniRef90_B8G4S5_316_540 R V P D - - - - - D M P P V Y A D Y E R L R Q V F T N L I E N A V K Y S P - - N G - G - - T - - - - UniRef90_E0FRK4_227_461 K K K I - - - - - D R V V I N G D V N R L K Q V L V N I I D N G I K A C S - - R G - K - - Y - - - - UniRef90_B1ZT44_154_390 Q V P V ------G L S A K V D A A K L R Q V L G N L I E N A I K Y G R - - E R - G - - R - - - - UniRef90_C9RTX6_347_579 E S P S ------G L V I R G D R N R M K Q I L L N L L A N A I T Y T P - - E H - G - - R - - - - UniRef90_A4XMJ6_338_561 S I L Q ------D I V A M V D R D K I E Q V L I N L I S N A V T Y V Q - - E G - G - - Q - - - - UniRef90_UPI00018511C5_286_519 E P I P ------E L T L E G D M N R F K Q V F I N L I N N A I S Y T G - - P G - G - - H - - - - UniRef90_A5ILS8_180_410 E C E ------D V V V R G N K E R L I Q M L L N L V D N A V K Y T S L K E K - G E K K - - - - UniRef90_B9K7H6_180_412 D C E ------N V T V K G N K E R L I Q M L L N L V D N A V K Y T S L K E K - G E K K - - - - UniRef90_F2I7J7_353_596 D N D L E - - - - A G I R F T T E E M R L K Q I L T N L I N N A I K Y N K A - E G - G - - Q - - - - UniRef90_B5YHW7_385_611 E I S K E - - - - A D I T V T A D E R K I K Q V L F N L V S N A V K F T P - - D G - G - - S - - - - UniRef90_C0A490_167_399 T L G A - - - - - A P G P L N F D A L K L T Q V F H N L L D N A L K Y T P - - P G - S - - R - - - - UniRef90_D6XVE0_357_597 E I D Q - - - - - S D T E A Y V D P D R I E Q V M T N L I D N A I R Y T S - - V N - G - - S - - - - UniRef90_A6CR52_338_570 H A D E ------A V L A E V D S F R I K Q V F I N L I G N A I T Y T P - - A G - G - - E - - - - UniRef90_F5SLG1_353_585 K S E E ------E F P V Q V D P D R F S Q I L L N L L S N A M T Y T P - - A G - G - - E - - - - UniRef90_A4FWN1_406_639 N V ------E K I T L E A D K D R I T Q V L T N L I E N A I K F S P - - A N - E - - S - - - - UniRef90_D3URW5_355_589 P E K T V - - - - P P V I I E T N R D Q L Q Q I L I N L L S N A I N Y T P - - V D - G - - K - - - - UniRef90_E8R548_187_428 V T E L P - - - - P Q F T I L A D E E A L R Q I L D N L I D N A I K Y S S - - D V - D P - W - - - - UniRef90_C9RD18_197_417 D L P P - - - - - G L P L V L G D P E L L T Q V F V N L I D N A L K Y T P - - V - - G - - R - - - - UniRef90_C1PEW1_349_587 E T S D - - - - - S D L T L E I D A D R I E Q V L T N L I D N A L R H T S - - S N - G - - Y - - - - UniRef90_Q1DCL6_267_509 E V S D - - - - - G L P A L D V D R A A V A G A L L N L L Q N A Y K Y S G P - D N - R - - R - - - - UniRef90_A8F5W9_184_414 D C E ------E V T I D G D Q D R L I Q M L L N L A D N A V K Y T S L K E S - G E K K - - - - UniRef90_Q2RFL3_239_485 E I P A - - - - - E I P E L A I S E S Y L N Q V L L N L I D N G I K Y T P - - A G - G - - R - - - - UniRef90_D1JAG2_243_467 K L P E - - - - - G L S S V K G D R E K L T Q V V I N L L N N A I K F T P - - R S - G - - E - - - - UniRef90_E5WJB7_351_584 Q R D E - - - - - K P V Y I E G D I H R L K Q V F I N I I S N A I S Y T P - - N Q - G - - V - - - - UniRef90_F6CIV3_222_456 E V P R - - - - - D L P S V Y G D P D M L A Q V L I N L L D N A I K Y T P - - P R - G - - S - - - - UniRef90_F6DKA0_218_449 D I P E ------L P E V P G D Q G L L V Q V M V N L V D N A I K Y T P - - E G - N - - S - - - - UniRef90_E3Z246_18_252 P E K T I - - - - P P I I I E T D R D K L Q Q I L I N L L S N A I N Y T P - - V D - G - - K - - - - UniRef90_B5YHI6_153_383 E I P P ------E T A I Y A D Q Y R M S Q I M I N L V D N A I K F T - - - E K - G - - F - - - - UniRef90_A9GF59_268_496 D A S A ------L P P V R C D R R A L E Q V L M N L L D N A I K Y A G - - E G - A - - H - - - - UniRef90_E8WRA5_348_584 G S C A ------P V S A M A D R G R L D Q V L I N L L E N A I K Y S G - - Q G - G - - R - - - - UniRef90_Q097K6_265_506 D V P S - - - - - G L P Q V E V D R H A V A G A L L N L L Q N A Y K Y S G - - Q D - K - - R - - - - UniRef90_E1KHP7_365_592 F S I G - - - - - D K P E V Y A D K D R I E Q V V L N V L T N A I K Y T P - - D K - G - - K - - - - UniRef90_A9AVU3_644_869 D V P D - - - - - D L P P M I A D P E R M R Q I V T N L I S N A Y K Y T R - - D G - G - - R - - - - UniRef90_A6UWZ1_410_640 K V ------E P I T A N L D K D K I T G V L T N L I E N A I K F S P - - V N - E - - N - - - - UniRef90_D4Y401_348_580 H A A K ------S I Y M E G D A N R L K Q I F I N L I T N A L T Y T P - - K G - G - - Q - - - - UniRef90_D7ATL0_341_566 D L Q E - - - - - T P R Y V Y I D R D K M E Q V I V N L V T N A I K Y T P - - E N - G - - M - - - - UniRef90_Q1PXZ9_292_526 V I Q E - - - - - D V K D I E A D R V K F K Q I L Y N L L S N S I K F T P - - Q N - G - - T - - - - UniRef90_E7M6U2_368_603 C V E N ------E L Y I E A D E D R L R Q I L I N L L S N G I S Y T P - - E G - G - - R - - - - UniRef90_D7BCF8_586_818 E I P P ------L P P V E A D P D R I G Q V M G N L L S N A F K F T P - - K G - G - - R - - - - UniRef90_D0MGH9_109_352 C V P E - - - - - N L P H V L G D R E R L R Q V L I N L V D N A I K Y N N - - P G - G - - F - - - - UniRef90_UPI000212A698_523_767 V D E V - - - - - K N D R V F A D R T K L K Q I M F N L L S N A I K F T P - - E A - G - - K - - - - UniRef90_E1K386_410_648 K I ------N D I I M K G D K D R I T Q V L T N L I E N A I K F S P - - V N - G - - K - - - - UniRef90_B9M7U2_251_475 P R ------N I P P L Q G D E A R L H Q V L T N L I S N G L K Y S Q - - A P - A - - R - - - - UniRef90_Q3AAG9_206_440 S L P E - - - - - N L P L V L A D G D M I S Q V L I N L I D N A I K Y T P - - A G - G - - K - - - - UniRef90_UPI0001E8932B_350_584 S K P K - - - - - K E L Y L F A D A S R I K Q V F I N L I N N A I A Y T P - - A G - G - - E - - - - UniRef90_C4G960_243_473 E S F R ------P V F C E I D E T K F S L A I T N L V E N A V K Y N N - - P G - G - - W - - - - UniRef90_C6J6K9_342_579 D V P E ------H L F I E A D E D R L R Q I F M N L L S N A I S Y S L - - E G - G - - K - - - - UniRef90_A0YQV3_1128_1360 I A T P - - - - - V P V I I N I D E L R I R Q V L I N L L S N A V K F T P - - E G - N - - H - - - 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Electronic Supplementary Material (ESI) for Medicinal Chemistry Communications This journal is © The Royal Society of Chemistry 2013

UniRef90_E3PT03_185_421 S P I D - - - - - N Q I Y L K S N P D L M K Q L I L N L I D N A I K Y S K - - E E - G - - F - - - - UniRef90_B7GGU1_348_587 T S N A - - - - - P V C Y M Y G D L H R L K Q I F I N L I N N A I A Y T P - - A G - G - - R - - - - UniRef90_Q39S62_358_588 S G L S - - - - - G A Q S V L A D P G R L E Q V L V N L L D N A I K Y T P - - E G - G - - A - - - - UniRef90_B8D0H3_363_592 D I K E - - - - - K L P F V Y L I P E Q I E Q V L I N L V D N G I K Y T E - - P G - G - - R - - - - UniRef90_F5L948_225_461 M P P D - - - - - E P A V V E A D P D R V Q Q I V I N L L S N A I T Y T P - - E G - G - - E - - - - UniRef90_E0NJE3_365_590 D V P M - - - - - D I N S M Y V D R H G A D Q V F R N I F S N A L K Y T R - - K G - G - - E - - - - UniRef90_A7II27_682_911 E A P E - - - - - T V P L L R A D P D R L T Q V V L N L I S N A V K F V P A - E G - G - - R - - - - UniRef90_B9DNB3_332_557 E I Q N ------H V M I D A E A S K I A Q V V T N L V S N A I N Y S S - - D E - S - - T - - - - UniRef90_A7HN49_181_412 K C E C ------K S T V Y G D F D R L V Q L V L N L V D N A V K Y T S I K E T - G E K K - - - - UniRef90_E6QIY0_358_593 D A ------A M H M V H A D Q E R I L Q V L A E L V S N A I K F S Q - - P H - T - - V - - - - UniRef90_F4L5H3_895_1123 S V S V - - - - - D F P A A S A D E N R L Q Q I L Y N L L G N A V K F T - - - E S - G - - Y - - - - UniRef90_A9AUY3_448_692 D I P E - - - - - G I P P I F A D K D K V R Q I L T N L L S N A I K Y S P - - N G - G - - Q - - - - UniRef90_Q1IKU6_785_1018 H S ------T R G I L Y A D R D R M L Q T L T N L L S N A I K F S K - - P D - N - - T - - - - UniRef90_B5YD58_456_687 P E ------Y P T F I L G D N A R L A Q V F H N L L D N A I K Y S P - - N G - G - - N - - - - UniRef90_UPI00016BFB3D_364_592 S Y N K - - - - N K E Y L I E G D P A R I G Q V F H N I L S N A I K Y T E - - D N - G - - Q - - - - UniRef90_E8SIU9_335_566 Q I E P ------N V T A M A D E N K I S Q V I V N L M T N A V N Y S P - - E N - R - - T - - - - UniRef90_B9E797_336_561 E L E K ------N L F V L A E P S K L K Q V M I N L L S N A I N Y S P - - E D - A - - E - - - - UniRef90_Q8EPE4_222_453 E V P D ------Q L T M R A D K D R M K Q V L I N L I D N S I H Y T P - - S G - G - - D - - - - UniRef90_D5DL55_355_590 N G K V E - - - - D E F E A M I D S D R M E Q V L T N L I D N A I R H T D - - D Y - G - - E - - - - UniRef90_E0HX50_173_410 D V D E ------G I F V E G D F D R L V Q L L L N L V D N A V K Y T F A K E H - G P K E - - - - UniRef90_B8DZU7_455_686 P E ------Y P T F V L G D S A R L T Q V F H N L L D N A I K Y S P - - N G - G - - N - - - - UniRef90_D6GSX7_369_596 N L L G - - - - - Q S R Q I W V D K T K M E Q V I I N I L S N A I K Y T E - - E N - G - - K - - - - UniRef90_D7CLL1_123_351 I F N R - - - - - D L P P V K A D E D L V G Q V L I N L I D N A I K Y T S - - P G - G - - K - - - - UniRef90_Q6LXP6_406_633 E V ------E D I A I E A D K D R I T Q V L T N L I E N A I K F S P - - A N - E - - S - - - - UniRef90_Q67LR3_257_496 D V P E - - - - - G L A R V M A D A D R L H Q V L D N L I S N A I K F S P - - Q G - S - - E - - - - UniRef90_A6LP23_177_414 V S P D ------K I E L I G D K D R L T Q M V L N L V D N A V K Y T S L K E K - G E K K - - - - UniRef90_B1HWE4_263_498 D I D G ------D V Q V M G D A N R I I Q I V T N L I T N A I T Y S P - - E N - T - - T - - - - UniRef90_Q2B2H9_351_585 S D Q S - - - - - G N G W I K G D P H R L K Q V F I N L L T N A I T Y T P - - Q G - G - - K - - - - UniRef90_B8FA30_356_583 D C P D ------D L T A V F D P T M I E Q A V V N L L D N A V K Y S E - - E H - G - - V - - - - UniRef90_B5YJP0_360_619 E I Q P - - - - - S L P F I N A D R E R L I Q V V I N L L S N A L K F T - - - E K - G - - Y - - - - UniRef90_F0JJT0_240_468 E V E P ------G L A V R A D P A H V R Q V L T N L A G N G V K F S E - - R G - G - - T - - - - UniRef90_E1KHE7_585_832 V D N A - - - - - D D T F G F I D K D L F E A V I A N L I S N A L K F T D - - S E - G - - Y - - - - UniRef90_C9LCS1_237_475 E S Y R ------P I V A E I D E V K L S L A L S N L V E N G I K Y N V - - E D - G - - W - - - - UniRef90_B7IEX9_176_421 V Y P D ------E L Y L V G D K D R L T Q M T L N L V D N A I K Y T S L K E K - G K K K - - - - UniRef90_Q8TMU8_474_720 E I D S - - - - - N L S R V Y A D K E R I L Q V L S N L V T N A V K F S N - - E N - G - - C - - - - UniRef90_Q71Y67_354_593 E L E T - - - - - P D L E Y S Y D P D R M E Q V L I N L I M N A I R H T G - - K E - G - - Y D G K V UniRef90_D5DMV7_352_585 D T L P - - - - - E E A W I D G D S Q R L M Q V F V N L I G N A L M Y T M - - P G - G - - T - - - - UniRef90_A5D189_222_456 N L P E - - - - - D L P V V Q G D P D M L S Q V L L N L I E N A V V Y T Q - - A G - G - - E - - - - UniRef90_C0Z7X8_357_585 P S P K - - - - - P D I W L M T D K D C L Q Q I I L N L L T N A I A Y T Q - - E G - G - - K - - - - UniRef90_D4TMU3_804_1043 Q N S N S S S N S S S I Q L W A D P D R I I Q T L T N L F S N A I K F S E - - P G - S - - T - - - - UniRef90_Q0W6Q5_299_531 D V P L - - - - - T L P M I S A D R S R I Q Q V L L N V L N N A I K Y T P - - D G - G - - Q - - - - UniRef90_B9E6M6_350_585 H Y S H ------H S K A W L D Y D K M I Q V I T N I I D N A L R Y T V - - A G - D - - V - - - - UniRef90_UPI000212C3B1_361_596 N V D G ------D F Y M E A D E D R L R Q I L I N L L S N G I S Y T P - - E G - G - - R - - - - UniRef90_A6UPU7_401_631 D I ------K D L L I N A D K D R I T Q V F T N L I E N A I K F S P - - A N - E - - S - - - - UniRef90_A5UQE0_447_687 D I P P - - - - - H L P P V Y A D R D K V R Q V L V N L I T N A V K Y S P - - N G - G - - E - - - - UniRef90_A1HSJ7_400_654 A V D A G - - - - V P P Q V Q V D V R R F K Q I M Y N L L S N A V K F T P - - D G - G - - A - - - - UniRef90_F2JII5_342_577 G Y D K - - - - K E E Y F I E G D L S R I R Q I L H N I L S N A I K Y S P - - E P - G - - T - - - - UniRef90_Q8R6U6_339_575 N L S E - - - - - T L Q K V N V D K D K V E Q M A M N I I N N A I K Y T P - - E G - G - - V - - - - UniRef90_Q8PT37_279_503 N V E P ------G F F V Y A D R T R F K Q I M Y N L V S N A V K F T Q - - K G - G - - S - - - - UniRef90_D8G5S6_939_1165 S S ------L S I S L W A D P D R I V Q T L I N L L S N A I K F S H - - T G - K - - I - - - - UniRef90_A8FJB5_372_608 N L P Q - - - - - R E I Y V E I D Q D K I T Q V L D N I I S N A M K Y S P - - E G - G - - H - - - - UniRef90_A5ITL6_318_551 D I E K ------D V I V K A Q E S K I A Q V I T N L L T N A I N Y S Y - - E D - G - - D - - - - UniRef90_F6B3A9_217_450 V L P D - - - - - K L P Q V P G D H G L L T Q V M V N L I D N A I K Y T P - - A S - G - - Q - - - - UniRef90_D9QVY1_356_592 D V P V - - - - - D I T G I K G S R G Q L E R L Y I N L V D N G I K Y T S - - E G - G - - Q - - - - UniRef90_A9AA11_406_633 E I ------E E I A I D A D K D R I T Q V L T N L I E N A I K F S P - - A N - E - - S - - - - UniRef90_D5E8Z5_365_588 I N N S - - - - - A I A K V W V D R V K F K Q I L H N L L S N A I K F T P - - E K - G - - E - - - - UniRef90_D2QCT5_672_903 C P T Q - - - - - A Q P V V D G D R D R L M Q V L I N L L S N A I K F S P - - A G T G - - H - - - - UniRef90_A3DHV5_362_596 F T I G - - - - - E E L E I V A D K D R M E Q V V L N I L T N A I K Y T P - - E G - G - - K - - - - UniRef90_B0ADS6_194_431 N F E D - - - - - E D V C I Y G F R D N I K Q I F L N L I D N G I K Y T P - - K D - G - - H - - - - UniRef90_E7RC70_372_606 Q L P K - - - - - E Q Y F V E I D P D K L T Q V I D N I I S N A L K Y S P - - E G - G - - K - - - - UniRef90_A0B593_141_369 R C E R - - - - - A N T L I E C D P K K I M Q V L S N L L T N A I K Y T P - - D R - G - - Q - - - - UniRef90_D4IVS0_239_469 E S F R ------P V V A E V D E V K F T L V V T N L V E N A I K Y N D - - E G - G - - W - - - - UniRef90_B1YMQ3_615_835 V ------G P I M I D A D A E K I K Q L L N N L L S N A I K Y S P - - D G - G - - N - - - - UniRef90_C1F3B6_554_791 E A ------E P M D L W V D A D R I L Q T L G N L I S N A I K F S P - - A G - A - - D - - - - UniRef90_E7RJV0_231_462 E I Q ------P V T V L G D A N R L I Q V M M N L L I N A V T Y S S - - N Y - T - - E - - - - UniRef90_D3UPQ2_354_596 E L E T - - - - - P N L E Y S Y D P D R M E Q V L I N L I M N A I R H T G - - K E - G - - Y Q G K V UniRef90_E0RD24_357_594 D I P D ------E L F M E A D E D K L Q Q I F L N L L S N G I N Y T L - - D G - G - - K - - - - UniRef90_F4LRR4_346_580 K L P E - - - - - N I A H I L S N E D S L L Q I M I N L L D N A I K Y T P - - E G - G - - T - - - - UniRef90_Q7NDS1_97_331 - - P G - - - - - A L P E V W A D Q D R L E Q I L T N L I D N A L K Y S E - - H G - A - - P - - - - UniRef90_Q647M8_182_410 K L A E ------M P N I I G D A E R L R Q A I G N L L N N A I K F S E - - K T - G - - K - - - - UniRef90_B8G6G1_479_712 R T ------P L P P V F A D R D K V K Q I I V N L L S N A I K Y S P - - E G - T - - E - - - - UniRef90_B7GKK3_359_585 E M N D ------E L I V S F D P D R V E Q V L T N L I D N A L R H T D - - E G - G - - E - - - - UniRef90_C1DVW6_110_330 Q V P N ------K F D V Y A D E Q K L S I A L K N L I E N A I K Y N K - - Q N - G - - K - - - - UniRef90_C4L472_342_574 K H E G ------T V V L Q A D L N R M K Q V I M N L V A N A I N Y S P - - E G - S - - R - - - - UniRef90_D7GPR0_250_485 E S K R ------D V S A D I D E V K F S L A V N N L V E N A V K Y N K - - E D - G - - W - - - - UniRef90_B4S8R4_490_736 H V E P - - - - - E T M Q V N A D P D A L K Q V V I N L A V N A I K F T P - - R D - G - - C - - - - UniRef90_A5GAH6_406_635 P S ------D L P R I C G D N K Q L R Q V F N N L V S N A V K Y S P - - K G - G - - A - - - - UniRef90_C6WZH9_504_741 K H F A ------D I E V F A D K E R L K Q V L T N L L T N A I K Y S P - - K A - N - - S - - - - UniRef90_B0TGE0_245_473 D V E T - - - - - N L P L L P L S P D N L K Q V L V N L T E N A I K Y T P - - E G - G - - Q - - - - UniRef90_D5E978_387_612 N N K F ------D I D I N L D K L K F I Q I M S N L L S N A V K F T P - - D K - G - - K - - - - UniRef90_F5LRU7_361_595 N V D E ------A L F L E A D E D R L R Q I L I N L M A N G I N Y T P - - E G - G - - R - - - - UniRef90_Q4A159_364_598 E V P T - - - - - E T I F T E I D P D K M T Q V F D N V I T N A M K Y S R - - G D - K - - R - - - -

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Input_pdb_SEQRES_2C2A - V - - K V I - - L D ------E - K D - - G G V L I I V E D N G I G I P D H A K UniRef90_A5IIT0_236_493 - V - - R V I - - L D ------E - K D - - G G V L I T V E D N G I G I P D H A K UniRef90_B9KAB5_220_473 - V - - K V V - - L D ------K - D E - - N G I L I V V E D N G I G I P E H A R UniRef90_UPI000210F96E_244_482 - V - - K I K - - L E ------R - L N - - D S V I I A V S D N G I G I P K E Y Q UniRef90_B7IDY9_224_462 - V - - N I S - - V E ------K - K E - - E N L S I I I E D N G I G I S Q E D K UniRef90_A6LN40_223_461 - V - - K I L - - V K ------K - L E - - D I L I I E V E D N G I G I P K S E Q UniRef90_A8F6Z9_244_486 - V - - K L S - - A E ------T - H Q - - D S V I I S V A D N G I G I E K Q H Q UniRef90_A7HK36_224_466 - V - - R I D - - V L ------D - E G - - E I V K I I V E D N G I G I P E S A F UniRef90_D5WTD2_380_614 - V - - D V R - - V L ------G T D P - - R E V K V E V A D T G V G I P P E D R UniRef90_Q67RF9_205_438 - I - - T L S - - A R ------R - D G - - D G V R I A V A D T G A G I P Q A D L UniRef90_B3E3A4_350_579 - V - - T V A - - A R ------L - E Q - - E R V V V A V S D T G I G I P A R D L UniRef90_C1P968_353_593 - I - - E I S - - L I ------E - R E - - N E L D L I V S D T G I G I S E K D L UniRef90_UPI000210FB4E_174_410 - V - - K V S - - A K ------L - Q D - - E S V V I K V E D T G P G I P K N A L UniRef90_D7AHN4_358_582 - I - - T L S - - A D ------E - A D - - G M V R V S V H D T G I G I P P K D L UniRef90_D5X969_353_585 - V - - V L S - - A T ------P - S G - - G G L K V S V K D T G I G I P P E S M UniRef90_D8PBL4_363_603 - I - - S M A - - I R ------N A T H M R A A T - P R - - P M I E I V V A D S G I G I P E A D R UniRef90_D7UVZ9_356_591 - V - - K V D - - V E ------E - S P - - H E V L F T V A D N G I G I P A K E I UniRef90_C5D651_348_580 - V - - E L M - - I E ------E - K E - - K E I L V H V K D T G I G I D E Q E I UniRef90_F4BLP5_336_567 - V - - T V T - - I R ------K - E N - - N Q A V I L V S D N G I G I P E D E Q UniRef90_Q3MGM2_1112_1344 - V - - W L V - - A Q ------Q - Y G - - D E L L V T V K D N G R G I P A D K L UniRef90_B8G4S5_316_540 - I - - R I G - - A R ------A - E G - - E M A I V Y V A D Q G I G I P P E E Q UniRef90_E0FRK4_227_461 - V - - K V F - - L D ------I - K D - - K K A V I R I E D Q G Q G I P Q E E I UniRef90_B1ZT44_154_390 - V - - V V Q - - G R ------A T G A - - A M V E I A V C D D G P G I P A E A R UniRef90_C9RTX6_347_579 - V - - A V E - - A E ------E - T E - - K E V L I H V K D T G I G I E E K E I UniRef90_A4XMJ6_338_561 - I - - N V V - - L Q ------K - E E - - D K I K I I V K D N G P G I P E E D L UniRef90_UPI00018511C5_286_519 - V - - K V F - - V K ------E - E R - - D E I T I K V Q D N G V G I A A S E L UniRef90_A5ILS8_180_410 - V - - W V R - - A Y ------D - T P - - D W V V L E V E D T G P G I P K E A Q UniRef90_B9K7H6_180_412 - V - - W V R - - A Y ------D - T P - - D W A V I E V E D T G P G I P K E A Q UniRef90_F2I7J7_353_596 - V - - W I S S T V T ------E - D D - - K Y V V V A I R D N G L G I P D E D I UniRef90_B5YHW7_385_611 - V - - K I T - - A E ------R - K E - - D M I E I V V E D T G I G I K K E D R UniRef90_C0A490_167_399 - I - - D I A - - I R ------P - K G - - S E I E I C V S D N G P G I P V A D L UniRef90_D6XVE0_357_597 - V - - K L R - - L E ------E - L P - - A G F R L D V E D T G A G I P E E D L UniRef90_A6CR52_338_570 - V - - S V S - - L K ------Q - S D - - S V I V I E V R D N G I G I E E S E F UniRef90_F5SLG1_353_585 - V - - I L S - - A G ------R - G E - - T D W W I R V A D T G I G I P G E D L UniRef90_A4FWN1_406_639 - I - - L V N - - G T ------L - E D - - E G L H L K V T D H G A G I P K K D M UniRef90_D3URW5_355_589 - V - - E V K - - L M ------E - R E - - S E V I I E V T D N G I G I P T K D I UniRef90_E8R548_187_428 - V - - K V V C R G D ------G - E A - - G M V A I D V I D N G L G I A S E E Q UniRef90_C9RD18_197_417 - V - - R I R - - G E ------Y - Q S - - G W V R I E V E D T G I G I P Q D C L UniRef90_C1PEW1_349_587 - V - - K V K - - E E ------E - A P - - G G V Y V H V E D N G S G I P D E D L UniRef90_Q1DCL6_267_509 - I - - T L Q - - V R ------G - S G - - K G V D L T V E D N G V G I A P Q E R UniRef90_A8F5W9_184_414 - V - - S I S - - V K ------K - E G - - S Q A V I R V S D T G P G M P R D A L UniRef90_Q2RFL3_239_485 - V - - T I R - - A A ------R - L G - - E L V Q V E V A D T G I G I P P E S L UniRef90_D1JAG2_243_467 - I - - S I K - - A I ------E - L N - - G Q V E V K V S D T G I G I P P E D L UniRef90_E5WJB7_351_584 - I - - Y I S - - A A ------K - T G - - S T V L T E I R D T G I G I E A S E I UniRef90_F6CIV3_222_456 - V - - T I R - - A M ------V - L E - - D Q L R V E V E D T G I G I P A E S L UniRef90_F6DKA0_218_449 - V - - T V G - - A S ------F - D G - - Q Q I R V F V K D T G I G I P E E S L UniRef90_E3Z246_18_252 - V - - E V K - - L I ------N - Q E - - A E V I I E V T D N G I G I P A K D I UniRef90_B5YHI6_153_383 - V - - K V R - - F F ------K - E N - - S K G V I S V E D T G I G I P K E H I UniRef90_A9GF59_268_496 - V - - T V R - - A R ------S - V D - - Q Q V T L A V A D D G P G I P P H H L UniRef90_E8WRA5_348_584 - I - - Q V E - - A A ------E - E G - - E M V R V S V R D N G I G I P E K D L UniRef90_Q097K6_265_506 - I - - A L S - - V R ------A - D R - - R W V A L S V E D N G V G I A P R D R UniRef90_E1KHP7_365_592 - I - - T V Y - - I G ------K - M Y - - S D A Y V K V V D S G I G I P E E D I UniRef90_A9AVU3_644_869 - I - - D V V - - V S ------N - G G - - D S V T L A V K D S G V G I A A D D Q UniRef90_A6UWZ1_410_640 - V - - T I E - - A F ------K - E N - - N M V H I T V K D N G P G I P K S E L UniRef90_D4Y401_348_580 - V - - E V I - - A E ------E - Q E - - E E T L V H V K D T G I G I E E A E I UniRef90_D7ATL0_341_566 - I - - K I M - - T E ------Y - D E - - S F A S L I V E D N G I G I P K E D L UniRef90_Q1PXZ9_292_526 - I - - T T N - - A A ------I - V D - - G K M Q V S V S D S G I G I K P E D R UniRef90_E7M6U2_368_603 - V - - S I G - - V E ------F V P S L D D N P - D N - - E R M R I R I S D T G I G I P E K D L UniRef90_D7BCF8_586_818 - V - - T L R - - A M ------L - E G - - D S L K I E V E D T G P G I P E S E R UniRef90_D0MGH9_109_352 - V - - E V R - - L Q ------E - Q D - - G S V R V A V V D N G I G I A P Q H I UniRef90_UPI000212A698_523_767 - V - - S V I - - I K ------Q - D D - - G G I V I S V S D T G I G I P L N M Q UniRef90_E1K386_410_648 - V - - E I Q - - A L ------K - E G - - N S V H I K I I D N G P G I P K K D L UniRef90_B9M7U2_251_475 - V - - T V G - - A E ------A - E G - - D Q V V V W V K D E G C G I P P E L Q UniRef90_Q3AAG9_206_440 - I - - E V T - - A A ------V - K G - - S W V E V V V K D T G I G I P E E S Q UniRef90_UPI0001E8932B_350_584 - V - - K V K - - V E ------E - V D - - K E V V I V V S D T G I G M E Q D E I UniRef90_C4G960_243_473 - V - - H V S - - L N ------A - D H - - Q Y C F V T V E D N G M G I P Q D S L UniRef90_C6J6K9_342_579 - V - - R V S - - A S ------I I - - - G E G G - D E - - E K V R I L V S D T G I G I P K K D L UniRef90_A0YQV3_1128_1360 - I L L K I E - - T E ------P - Q N - - N C V H L S V T D T G I G I A P E D Q

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V - - W V R - - V A ------D - K M - - E D I L I E V Q D Q G V G I P P E H L UniRef90_D6GSX7_369_596 - I - - S L S - - L F ------V - S E - - G I L D I V I E D N G I G I P K E D V UniRef90_D7CLL1_123_351 - I - - V I R - - V K ------R - G G - - D Q V F T S I T D T G T G I P Q E S L UniRef90_Q6LXP6_406_633 - I - - L V S - - G V ------L - E D - - E H I H L K V T D R G A G I P K K D M UniRef90_Q67LR3_257_496 - V - - L I R - - A R ------E - T G - - D G V R F D V I D R G P G I P A D Q T UniRef90_A6LP23_177_414 - V - - L V E - - A Y ------K - D N - - N H V K L I V K D T G V G I P E K A Q UniRef90_B1HWE4_263_498 - V - - S I R - - L K ------E - N E - - T Y G I I E I E D Q G I G I E K H E I UniRef90_Q2B2H9_351_585 - I - - S V S - - L E ------E - K E - - D K V Q V E V K D T G M G I D Q D E I UniRef90_B8FA30_356_583 - V - - R V G - - A K ------A - E G - - G E V L I W V E D E G P G I S E E H L UniRef90_B5YJP0_360_619 - V - - K C K - - T A ------L - N A - - D E I V V S V E D S G I G I P E E E K UniRef90_F0JJT0_240_468 - V - - R L I - - A E ------R - S G - - R E V L F S V A D D G P G I P V D E Q UniRef90_E1KHE7_585_832 - I - - I I E - - L N ------K - L D - - T S F E I V V K D S G I G I P K D K L UniRef90_C9LCS1_237_475 - V - - H V T - - L N ------A - D H - - K Y F Y V S V E D S G I G I P Q E S I UniRef90_B7IEX9_176_421 - V - - T V E - - A W ------K - E N - - N S I K L V V K D T G V G I P E K A Q UniRef90_Q8TMU8_474_720 - V - - K V K - - A V ------Q - M D - - G F L K I T V A D D G I G I A A A D H UniRef90_Q71Y67_354_593 I L - - K Q T - - I D ------E - A R - - S N L V I T V S D N G S G I A E E D I UniRef90_D5DMV7_352_585 - V - - H V S - - L E ------E - E E - - E T I T V H V Q D T G I G I D S D E I UniRef90_A5D189_222_456 - V - - S I S - - A A ------A - T Q - - D E M K V D V K D N G I G I P P E S L UniRef90_C0Z7X8_357_585 - I - - S I K - - T E ------A - D S - - E N I T I Q V M D T G I G I P E K E L UniRef90_D4TMU3_804_1043 - V - - Y L M - - T E ------L - Q K - - D Q V L V T V Q D T G R G I P E D K L UniRef90_Q0W6Q5_299_531 - I - - S I S - - V R ------D - E C - - D H L L I A V R D T G I G I P K E D I UniRef90_B9E6M6_350_585 - I - - S I H - - T D ------E - D D - - E N L I I R I S D T G V G I A P E H I UniRef90_UPI000212C3B1_361_596 - V - - R L K - - V E ------Q L V S G K E V T - E H - - D K V R F T I A D T G I G I P K K D L UniRef90_A6UPU7_401_631 - I - - M I I - - G K ------E T E N - - G D V H I T V K D N G A G I P K K D L UniRef90_A5UQE0_447_687 - I - - R L T - - I S - - D N V E L P P D H - - - P - R G - - K F V R V A V S D Q G I G I A P E D L UniRef90_A1HSJ7_400_654 - I - - K V E - - C R ------D - A G - - E W L E I S V E D T G I G I A A T H A UniRef90_F2JII5_342_577 - L - - G V Y - - M K ------K - E N - - A Y V I V E I T D T G M G I P E E D L UniRef90_Q8R6U6_339_575 - I - - E I S - - T A ------Y - D E - - E G V T F T V K D N G I G I P K E D L UniRef90_Q8PT37_279_503 - V - - E V L - - G I ------V - S E - - K G V R V S V S D T G I G I S K D E I UniRef90_D8G5S6_939_1165 - V - - W L T - - V Q ------Q - Q D - - R H L L F I V K D E G R G I P T E K L UniRef90_A8FJB5_372_608 - I - - T F T - - V D ------L - D E E K S L V L F S V K D E G I G I P K K D M UniRef90_A5ITL6_318_551 - I - - N V R - - V Y ------R - D D - - F R V I F E V Q D F G I G I K L E D Q UniRef90_F6B3A9_217_450 - V - - K V G - - V N ------L - N R - - E K V R V Y V A D T G I G I P Q E D L UniRef90_D9QVY1_356_592 - V - - K I K - - V Y ------E - D E - - D R V W S E I I D T G M G I P E E D L UniRef90_A9AA11_406_633 - I - - M I S - - A D ------L - E D - - E H V H L R V T D H G A G I P K K D M UniRef90_D5E8Z5_365_588 - V - - K I Y - - L S ------T - D D - - G T A Q I S V A D T G I G I P A E K I UniRef90_D2QCT5_672_903 - V - - T V C - - L T ------I - R D - - E R V N L T V R D N G I G I E P D V Q UniRef90_A3DHV5_362_596 - I - - T V Y - - I G ------R - M Y - - S E V Y V K V V D S G I G I P R E D L UniRef90_B0ADS6_194_431 - I - - E V V Q H Y D ------E - N R - - Q N I I L E F K D N G I G I P K E S L UniRef90_E7RC70_372_606 - V - - R F N - - M T ------V - E E - - G Y L L I Q I S D E G M G I P K E N V UniRef90_A0B593_141_369 - I - - E V V - - L G ------G - D A - - E N V L V S I R D N G I G I R E E D K UniRef90_D4IVS0_239_469 - V - - H I S - - L N ------S - D H - - Q F F Y I K V E D N G L G I P E N S V UniRef90_B1YMQ3_615_835 - V - - A I R - - I E ------N - H D - - G F A E I T I R D Q G I G I P Q E A M UniRef90_C1F3B6_554_791 - V - - L V R - - A S ------V - R G - K A E A V I E V R D H G R G I P P E K I UniRef90_E7RJV0_231_462 - I - - T I R - - L F ------R - K D - - N R A I I Q V E D Q G I G I E S S E I UniRef90_D3UPQ2_354_596 V L - - K Q T - - I D ------E - T N - - N K L I I T V S D N G S G I A E E D I UniRef90_E0RD24_357_594 - V - - K I K - - V L ------T I - - - Q R E N - D T - - E K V V F T V S D T G I G I P K K D L UniRef90_F4LRR4_346_580 - I - - S I M - - V E ------E - T L - - E N V L I T V A D N G I G I A E D E L UniRef90_Q7NDS1_97_331 - V - - C V S - - A D ------L D P - - - - - E - D R - - N V L W I A V R D L G I G I P E E N L UniRef90_Q647M8_182_410 - V - - I I E - - T K ------R - L G - - K N V Q F S I T D Y G I G I S K A D Q UniRef90_B8G6G1_479_712 - I - - Q L I - - V R Q A E A S D L P A G H - - - P - A G - - Q W M L I T V Q D Q G I G I E P E D Q UniRef90_B7GKK3_359_585 - V - - R V I - - V D ------A - D E - - E V V R I S V Q D S G S G I P E E D L UniRef90_C1DVW6_110_330 - V - - I V K - - A V ------K - D S - - K Y T T I T V E D T G I G I P E E S I UniRef90_C4L472_342_574 - V - - E I A - - V E ------A - K A - - D S Y K L R V K D N G I G I A E K E V UniRef90_D7GPR0_250_485 - V - - R V T - - L D ------A - D H - - K F F Y L K V A D S G I G I P A E F K UniRef90_B4S8R4_490_736 - V - - R V S - - L S ------N - D A - - H W M V L T V K D S G V G I P E S D Y UniRef90_A5GAH6_406_635 - V - - R V A - - A R ------R - E K - - D C V V I T V R D E G I G I S P Q A V UniRef90_C6WZH9_504_741 - V - - N V E - - L W ------V - E D - - G R G I V S V E D F G I G M E A S E L UniRef90_B0TGE0_245_473 - V - - S V R - - A T ------R - G C - - D S V I L E V Q D T G I G I P E E S L UniRef90_D5E978_387_612 - V - - S V D - - I D ------F - V A - - E Y V Q V S V T D S G I G I P E H K L UniRef90_F5LRU7_361_595 - V - - S V A - - A E ------L A G S G T E - G - E D - - E R I R I S I K D T G I G I P K K D L UniRef90_Q4A159_364_598 - V - - E F H - - V K ------Q - N A L Y N R M T I R V K D N G I G I P I N K V

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F Box ______G3 ______ê Input_pdb_SEQRES_2C2A D R I F E Q F Y R V D S S L T Y E V P - G T G L G L A I T K E I V E L H G G R I W V E - S E V G K G UniRef90_A5IIT0_236_493 D R I F E Q F Y R V D S S L T Y E V P - G T G L G L T I T K E I V E L H G G K I W V E - S E V G K G UniRef90_B9KAB5_220_473 E K I F E Q F Y R V D S S L T Y E V S - G T G L G L A I T K E I V E L H G G R I W V E - S E E G K G UniRef90_UPI000210F96E_244_482 S R I F E K F F R V Q S F K D Y K V E - G T G L G L T I C K E I V E L H G G K I W F E - S E P G K G UniRef90_B7IDY9_224_462 E K I F E K F Y R G D R S L T Y E V P - G T G L G L T I V Q E I I K L H G G K I N V N - S T L G E G UniRef90_A6LN40_223_461 E K I F E K F Y K I D R S L T Y E V P - G T G M G L A I V K E I V R L H G G N I E V E - S E E K K G UniRef90_A8F6Z9_244_486 N K I F E K F F R A D S V F D Y R T E - G T G L G L A I S K E I V E L H G G Q I W F E - S K P H E G UniRef90_A7HK36_224_466 D K I F E R F Y R V D N E L T Y A V P - G T G L G L A I V K E I V E L H E G N I L V E - S E V G K Y UniRef90_D5WTD2_380_614 D R V F E R F Y R V D K A R A R T T G - G T G L G L A I V K H V V Q L H G G R V G V E - S E V G K G UniRef90_Q67RF9_205_438 G R I F E R F Y R V D K A R S R A T G - G T G L G L A I A K H I V E A H G G T I G V E - S E V G K G UniRef90_B3E3A4_350_579 P R I F E R F Y R V D E G R S R E Q G - G T G L G L A I V K H I V Q L H G G E V Q V A - S E A G K G UniRef90_C1P968_353_593 P R I F E R F Y R V D K A R S R Q S G - G T G L G L A I V K H L V E S Y H G K I R V E - S E E G K G UniRef90_UPI000210FB4E_174_410 E R I F D R F Y R V D K G R S R K M G - G A G L G L S I V K T I V D R H N G K I Y V E - S E V G V G UniRef90_D7AHN4_358_582 P R I F E R F Y R V D A A R S R D E G - G T G L G L S I V K H I I Q L H G G N I T V E - S E H G K G UniRef90_D5X969_353_585 S R L F E R F Y R V D K A R S R E L G - G T G L G L A I V K H A L E A H G G T I K V E - S Q V G M G UniRef90_D8PBL4_363_603 P R V F E R F Y R V D K A R S R E L G - G T G L G L A I V K H I V E A H S G Q V W V E - G N T P R G UniRef90_D7UVZ9_356_591 E R V F E R F Y R V D K A R S R Y S G - G T G L G L S I V K H L T E Q L G G R I E V A - S V E G E G UniRef90_C5D651_348_580 P R I F E R F Y R V D K A R G R N S G - G T G L G L A I V K H L V E A H H G H I T V K - S T V G K G UniRef90_F4BLP5_336_567 D R I F E R F Y R V D K A R S R N S G - G T G L G L S I V K Y L V E N L N G S I A V E - S K L G L G UniRef90_Q3MGM2_1112_1344 D S I F E R F Q Q V D S S D S R N H D - G T G L G L A I C Q S I V Q Q H G G R I W A E - S V L S E G UniRef90_B8G4S5_316_540 D L I F E R F Y R V D N R L R R D R P - G S G L G L Y I T R A I V E A H G G R I W V E - S Q V G R G UniRef90_E0FRK4_227_461 K Y I F D K F Y R - - - G K N N K Y S - G T G L G L A I S K K I I E E H K G T I T V E - S E V G K G UniRef90_B1ZT44_154_390 S R V F E R F Y R V D K A R S R E Q G - G T G L G L S I V K N L V Q A H G G E V R V E - S E L G R G UniRef90_C9RTX6_347_579 P R I F E R F Y R V D K A R S R D S G - G T G L G L A I V K H L V E A H H G Y I T V A - S K V G R G UniRef90_A4XMJ6_338_561 P R I F E R F Y R V D K A R S R E L G - G S G L G L S I A D E I V K A H G G K I L V E - S K V G S G UniRef90_UPI00018511C5_286_519 P R I F E R F Y R I D K A R S R N S G - G T G L G L A I V K H I V E A H H G E I D V E - S S E G V G UniRef90_A5ILS8_180_410 S R I F E K F Y R V D K A R S R K M G - G T G L G L T I V K T I V D K H G G R I E V E - S E I N Q G UniRef90_B9K7H6_180_412 S R I F E K F F R V D K A R S R K M G - G T G L G L T I V K T I V D R H G G K I E V E - S E V G Q G UniRef90_F2I7J7_353_596 P R I F E R F Y R V D K T R S T A S G - G T G L G L S I V R N L V A S M S G K I D V V - S E L N E G UniRef90_B5YHW7_385_611 D K L F Q P F S Q L E T T Y T K K Y Q - G T G L G L A L S K S L V E L H G G K I W C E - S E Y G K G UniRef90_C0A490_167_399 P H I F E R F Y R V D K G R S R E T G - G T G L G L S I V K H I V Q L H G G R V W V E - S E P G R G UniRef90_D6XVE0_357_597 P F V F E R F Y K A D K A R T R G R A - G T G L G L A I V K N I V E A H K G R V S A H - S R M G E G UniRef90_A6CR52_338_570 P R I F E R F Y R V D K A R S R D S G - G T G L G L A I V K H L I E A H G G T I G V E - S K V N E G UniRef90_F5SLG1_353_585 P R I F E R F Y R V D K A R S R E S G - G T G L G L A I V K H L V E A H Q G E I Q V T - S R A G K G UniRef90_A4FWN1_406_639 E K V F D R F Y Q V D S S T K R K K G - G S G L G L A V C K S I V E A H G G S I W V E - S E L G K G UniRef90_D3URW5_355_589 D R V F E R F Y R V D K A R S R H S G - G T G L G L S I V K H L V E N C G G R I E V E - S Q E E V G UniRef90_E8R548_187_428 T R I F E R F Y R V D K A R S R E R G - G T G L G L A I V K H L V Q A L R G E I E L Q - S R V G A G UniRef90_C9RD18_197_417 P R V F E R F F R V D R A R S R A S G - G T G L G L S I V K H I V E L H G G K V G V E - S E L G K G UniRef90_C1PEW1_349_587 P F V F E R F Y K A D K A R T R G K S - G T G L G L A I A K N I V E G H G G R I F V K - S K L G E G UniRef90_Q1DCL6_267_509 T R I F E R F Y R V D N L L T R R T E - G S G L G L A I T R R I I E T H G G R I S V Q - S E P G K G UniRef90_A8F5W9_184_414 N R I F D R F Y R V D K G R S R K M G - G S G L G L S I V K T I V D R H N G Q I F V E - S E P G A G UniRef90_Q2RFL3_239_485 P R V F E R F Y R V D K A R S R E M G - G T G L G L A I V K H I V E S H G G S I S V T - S R P G Q G UniRef90_D1JAG2_243_467 E K V F D K F Y Q V D S T L T R E A G - G T G L G L A I C K G I I E A H N G H I W A E - S E L G K G UniRef90_E5WJB7_351_584 P R I F E R F Y R V D K A R S R N S G - G T G L G L A I V K H L V E A H K G S I S V K - S E V G K G UniRef90_F6CIV3_222_456 P R I F E R F Y R V D K A R S R E L G - G F G I G L A I V K H I I R A H G G K I E V E - S T P G K G UniRef90_F6DKA0_218_449 S R V F E R F Y R V D K A R S R D V G - G T G L G L S I S K H I V E A H G G K I W A E - S H - S E G UniRef90_E3Z246_18_252 D R V F E R F Y R V D K A R S R H S G - G T G L G L S I V K H L V E N C G G R I E V E - S Q E E V G UniRef90_B5YHI6_153_383 H R I G E R F Y R V D K A R S R Q L G - G T G L G L A I V K H L V L A H G W Q L Q I E - S E V E K G UniRef90_A9GF59_268_496 G R I F E R F Y R V D A G R S R D L G - G T G L G L A I V K H L V E L M N G S I E V E - S A I G R G UniRef90_E8WRA5_348_584 P R L F E R F Y R V D E A R S R E R G - G T G L G L S I V K H I V M A H G G S V F V E - S T V G K G UniRef90_Q097K6_265_506 Q R I F E R F Y R V D N L L T R K T E - G S G L G L A I T K R I I E A H G G R I S V Q - S K L G K G UniRef90_E1KHP7_365_592 K R V F E R F Y R V D K A R S R E M G - G T G L G L S I A K E I I E A H K G S I S I S - S Q L G K G UniRef90_A9AVU3_644_869 K H I F T R F F R S E N P L K E Q A G - G T G L G L N I T K S L V E L H G G K I W F D - S E E G R G UniRef90_A6UWZ1_410_640 T K I F D I F Y Q V N S S A K R I K S - G S G L G L A I C K S I V E S H G G K I W V E - S K F G K E UniRef90_D4Y401_348_580 P R I F E R F Y R V D K A R S R H S G - G T G L G L A I V K H L V E A H H G H I T V K - S A V G K G UniRef90_D7ATL0_341_566 P R I F E R F Y R V D K A R S R E L G - G T G L G L S I V K Q I V E L H K G E V N I E - S E V G K G UniRef90_Q1PXZ9_292_526 E K V F K E F W Q A D S S F S R K Y E - G T G L G L A L T R R I V E M H G G K I W L K - S E Y G K G UniRef90_E7M6U2_368_603 P R I F E R F Y R V D K A R S R S S G - G T G L G L S I V K H L T E L H H G T I S V E - S E A G K G UniRef90_D7BCF8_586_818 S R L F Q R Y G R T Q S A V S R G V S - G T G L G L Y I S K A I V E A H G G R I W V E - S E V G K G UniRef90_D0MGH9_109_352 P R L T E R F Y R V D R S R S R E Q G - G T G L G L A I V K H I L N A H Q T R L E I E - S T P G K G UniRef90_UPI000212A698_523_767 E N I F D L F T Q V D G S I K R K Y D - G T G L G L A I V K Q Y V E M H N G K V W V E - S E E D K G UniRef90_E1K386_410_648 D R I F D R F Y Q V D S P E K R I K G - G S G L G L A V C K S I I E T H G G T I W V E - S K L G S G UniRef90_B9M7U2_251_475 E K I F E K F Y R I D N T D R R H I G - G T G L G L A L V R E I V A A H G G R V W V T - S E V G R G UniRef90_Q3AAG9_206_440 K R I F E R F Y R V D K A R S R E L G - G T G L G L A I V K H I I E L H N G K V W V K - S K V G E G UniRef90_UPI0001E8932B_350_584 P R I F E R F Y R V D K A R S R N S G - G T G L G L A I V K H I V E A H H G S I S V T - S E L N K G UniRef90_C4G960_243_473 D R I F E R F Y R V D K S H S R E I G - G T G L G L A I T Q N A I R M H H G E I R V A - S E L G Q G UniRef90_C6J6K9_342_579 P R I F E R F Y R V D K A R S R S S G - G T G L G L S I V K H L V D L H R G T I R V E - S K V G E G UniRef90_A0YQV3_1128_1360 V R L F E P F V Q I D S S L S R R Y S - G T G L G L A L V R Q I T Q M H A G T V S L D - S E V G R G

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Electronic Supplementary Material (ESI) for Medicinal Chemistry Communications This journal is © The Royal Society of Chemistry 2013

UniRef90_E3PT03_185_421 D R I F E R F Y R V D K A R S K K V G - G T G L G L A I V K H I V L N L N G N I K V H - S E L N K G UniRef90_B7GGU1_348_587 P R I F E R F Y R V D K A R S R N S G - G T G L G L A I V K H L V E A H H G T I S V K - S E V G I G UniRef90_Q39S62_358_588 P R I F E R F Y R V D T A R S R D E G - G T G L G L S I V K H I V Q L H G G A V G V E - S E P G K G UniRef90_B8D0H3_363_592 G R I F E R F Y R V D K A R S R S M G - G T G I G L S I V K H I I K N H D S E I K V E - S E P G K G UniRef90_F5L948_225_461 P R I F E R F Y R V D R A R S R A S G - G T G L G L A I V K H L V E A H R G E I T V E - S E P G K G UniRef90_E0NJE3_365_590 N K I F E R F Y R V E K S R S R E M G - G T G L G L S I A K E I L E S M G G R I S I E - S E I G V G UniRef90_A7II27_682_911 D T I F E K F R Q G G D A L T R P P - - G T G L G L P I S R R I V D H F G G R M W L E - N Q D G S G UniRef90_B9DNB3_332_557 K H V F E R F Y R V D K A R S R D S G - G T G L G L S I T K H I V E A Y Q G R I Q I E - S E P D V G UniRef90_A7HN49_181_412 K R L F E R F Y R V D K A R S R K V G - G T G L G L S I V K M I A D K H N A T I S F E - S K V G E G UniRef90_E6QIY0_358_593 E V I F E R F H Q G D A S D A R A L G - G T G M G L A L C R Q I V R Q H G G R I W A E - S E P D K G UniRef90_F4L5H3_895_1123 D A I F Q E F T Q G D A S T T R A F S - G T G L G L S I S K R L V E L H G G T M W L E - S E I D Q G UniRef90_A9AUY3_448_692 P K L F T R F F R V D N S T T R K I G - G T G L G L S I T K A L I E L H G G R I W A T - S T L G R G UniRef90_Q1IKU6_785_1018 Q T I F E R F Q Q V D A S D S R D K G - G T G L G L A I C R S I V Q Q H G G S I W V D - S I D G K G UniRef90_B5YD58_456_687 P H I F D R F Y R V D S S L R K S T S - G T G L G L S I V K S I I E A H G G K I S V A - S K V G E G UniRef90_UPI00016BFB3D_364_592 E R I F E R F Y R A D K A R S R K M G - G T G L G L S I A K E M V E L H G G S I K M E - S A L G H G UniRef90_E8SIU9_335_566 Y R I F E R F Y R V D K A R S R D S G - G T G L G L S I T K H I I E A Y Q G N I E V A - S E L G K G UniRef90_B9E797_336_561 T R I F E R F Y R V D K A R S R D S G - G T G L G L A I V K H I I E V F N G E I D V E - S E L G K G UniRef90_Q8EPE4_222_453 T R V F E R F Y R V D K A R S R N T G - G T G L G L A I V K H I V E V H K G K I D V E - S T L N Q G UniRef90_D5DL55_355_590 P F V F E R F Y K A D K A R T R G K S - G T G L G L A I A K N I V E A H Q G I I A V E - S E L N E G UniRef90_E0HX50_173_410 K H I F E R F Y R V D K A R S R K M G - G T G L G L A I T R F I V E K H G G T I S L E - S E Y G T G UniRef90_B8DZU7_455_686 P H I F D R F Y R V D S S L R K S T S - G T G L G L S I V K S I V E A H G G K I S A T - S K V G E G UniRef90_D6GSX7_369_596 E H I F D R F Y R V D K G R S R Q Q G - G T G L G L S I A K H I V E E H G G S I S V R - S D F G K G UniRef90_D7CLL1_123_351 P R L F E R F Y R V D K A R S R E L G - G T G L G L A I V K H I V E S H G G E V F V E - S E L G K G UniRef90_Q6LXP6_406_633 E K I F N R F Y Q V D S S T K R K K G - G S G L G L A V C K S I V E A H K G S I W V E - S E L G K G UniRef90_Q67LR3_257_496 G L I F E R F Y R V D N A A S R K T G - G T G L G L T I C K A I V E E H G G Q I W V E - S A L G E G UniRef90_A6LP23_177_414 K K L F E R F Y R V D K A R S R K M G - G T G L G L S I V K T I V E K H N G T I E F T - S K E G V G UniRef90_B1HWE4_263_498 A R V F E R F Y R V D R A R S R N S G - G T G L G L A I V K H L V E A H H G R I Q V E - S E V G V G UniRef90_Q2B2H9_351_585 P R I F E R F Y R I D K A R S R N S G - G T G L G L A I V K H L V E A H K G S I T V E - S E V G K G UniRef90_B8FA30_356_583 P R L F E R F Y R V D K A R S R N L G - G T G L G L A I V K H I M A A H G G H V S V K - S E K G K G UniRef90_B5YJP0_360_619 E R I F E K F K Q V G D L I R G K P K - G T G L G L A I S K Q I V E A H G G K I W V E - S E L G K G UniRef90_F0JJT0_240_468 E R I F L K Y Y R - E P G V R D S I D - G A G L G L A I A R R I V L A H D G R I W V E - S E P G R G UniRef90_E1KHE7_585_832 D T I F D R F S Q I E N S K S S K V R - G T G I G L A Y T K E I V E L H E G K I S V S - S I L G K G UniRef90_C9LCS1_237_475 D R I F E R F Y R V D K S H S R E I G - G T G L G L A I T R N A I V M H R G A I K V K - S E E H K G UniRef90_B7IEX9_176_421 K K L F E R F Y R V D K A R S R K M G - G T G L G L S I V K T I V E K H N G V I E F T - S K E G V G UniRef90_Q8TMU8_474_720 E K L F K P F S Q I D S S F S K R Y Q - G T G L G L A L V K E I V Q L H G G T V W F E - S E V G K G UniRef90_Q71Y67_354_593 P Y L F E R F Y K V D K A R K R G K A V G T G I G L A I V K N I V E A H N G K I S V E - S E L G K G UniRef90_D5DMV7_352_585 S R I F E R F Y R V D K A R S R N S G - G T G L G L A I V K H L V E A H K G E I E V K - S E V N K G UniRef90_A5D189_222_456 S R V F E R F Y R V D K A R S R E Q G - G T G L G L S I V K H I I D A H R G S V Q V E - S K V G I G UniRef90_C0Z7X8_357_585 T R I F E R F Y R V D K A R S R D S G - G T G L G L A I V K H L V E N L H G H I S V E - S K E G R G UniRef90_D4TMU3_804_1043 E S I F E R F Q Q V D S S D S R N H D - G T G L G L A I C K S I V Q Q H G G K I W V K - S V L G Q G UniRef90_Q0W6Q5_299_531 E N I F S G F Y H S G Y K L S Y E Y K - G A G L G L A I S R K I V E S H G G K I W A D - S E P G K G UniRef90_B9E6M6_350_585 D N I F E R F Y K V D Q A R T R G K H - G T G L G L F I V K S I V E G H H G S I N V D - S T V G K G UniRef90_UPI000212C3B1_361_596 P R I F E R F Y R V D K A R S R S S G - G T G L G L S I V K H L V E L H K G T I R V E - S E V G V G UniRef90_A6UPU7_401_631 E K I F D Q F Y Q V D S S T K R K K G - G S G L G L A V C K S I I Q A H G G T I W V E - S E L G R G UniRef90_A5UQE0_447_687 P R I W E R F Y R V D N G N T R R I G - G T G L G L S I A K A L V E L H G G R I W A E - S K L N K G UniRef90_A1HSJ7_400_654 E H I F E P F Y Q V S G N L T A K T P - G T G L G L A I T R Q L V E L H G G R I W L E R S E P G Q G UniRef90_F2JII5_342_577 E R I F E R F Y R V D K A R S R K M G - G T G L G L S I A K E L M L L H G G D I K I E - S Q L G Q G UniRef90_Q8R6U6_339_575 P R I F E R F Y R V D K A R S R E L G - G T G L G L S I V K Q I V E L H K G K V K I E - S E L G K G UniRef90_Q8PT37_279_503 K Q L F K P F K Q I D S T L S R K Y E - G T G L G L V L S K K F V E M H G G R I W V E - S E P G K G UniRef90_D8G5S6_939_1165 E S I F E R F Q Q V D S S D S R N H E - G T G L G L A I C R S I V Q Q H D G H I W V E - S V L G E G UniRef90_A8FJB5_372_608 D K I F E R F Y R V D K A R T R K L G - G T G L G L A I A K E M V Q A H G G D I W A D - S I E G K G UniRef90_A5ITL6_318_551 Q R I F E R F Y R V D K A R S R D S G - G T G L G L S I T K H I V E A H Q G N I E V N - S Q V G K G UniRef90_F6B3A9_217_450 P R I F E R F Y R V D K A R S R V M G - G T G L G L A I C K H I V E V H G G Q I E V E - S G P G - G UniRef90_D9QVY1_356_592 P R I F E R F Y R V D K T R S R K L G - G T G L G L S I V K H I L E R H N G G I E V E - S K V E E G UniRef90_A9AA11_406_633 E K V F N R F Y Q V D S S T K R K K G - G S G L G L A V C K S I V E A H K G S I W V E - S E L G K G UniRef90_D5E8Z5_365_588 E D I F D P F K Q V N S S S S R E Y E - G T G L G L A L V K K Y V E M H D G E I W V E - S E V G A G UniRef90_D2QCT5_672_903 Q L I F E K F Y Q A T N Q T L R K P K - G S G L G L A I T K K I I A L H N G Q I T V S - S V P G E G UniRef90_A3DHV5_362_596 G R I F E R F Y R T D K A R S R E M G - G T G L G L A I A K E I V E A H K G S I S V A - S E P G K G UniRef90_B0ADS6_194_431 N R I F E R F Y R V D K A R S R D I G - G T G L G L A I T K H M V K S L G G N I T V E - S I L G I G UniRef90_E7RC70_372_606 D R I F D R F Y R V D R A R S R E M G - G T G L G L A I S K E M I N A H G G V I W A E - S K L G K G UniRef90_A0B593_141_369 D R I F E K F F V M S N E K S A D I - - G M G L G L S I T K D I V E A H G G R I W F E - S R F G E G UniRef90_D4IVS0_239_469 D H I F E R F Y R A D K S H S R E I G - G T G L G L A I T K S A I A M H N G E I K V R - S K L G E G UniRef90_B1YMQ3_615_835 S K L F D K F Y R V D N S E T R K I G - G T G L G L S I C K E I V K H H N G T I D V E - S T I G A G UniRef90_C1F3B6_554_791 S L I F E R F Q Q V D A S D S R A M G - G T G L G L A I C R R I V R Q H G G Q I W V E - S E V G K G UniRef90_E7RJV0_231_462 G R L F E R F Y R V D R A R S R N S G - G T G L G L S I V K H L I E A H H G H V E V D - S T V G V G UniRef90_D3UPQ2_354_596 P Y L F E R F Y K A D K A R K R G K A V G T G I G L A I V K N I V E A H G G K I S V K - S E L G K G UniRef90_E0RD24_357_594 P R I F E R F Y R V D K G R S R N S G - G T G L G L S I V K H L V D L H H G T L S V E - S E L G L G UniRef90_F4LRR4_346_580 D R I F E R F Y R V D R A R S G E I G - G T G L G L A M V K H L V K G L E G W I K V E - S E L E K G UniRef90_Q7NDS1_97_331 D Q I F N R F S R I D S P L T R E R E - G T G L G L Y I T K S L V E S L G G T I H V E - S R Y G V G UniRef90_Q647M8_182_410 K K L F K P F T Q I D S S M G R E H V - G T G L G L A I T K G I I Q A H N G K I W A E - S E L G K G UniRef90_B8G6G1_479_712 A R L F E R F H R V D N S N T R Q K S - G V G L G L Y I T R L L V E L H G G R I W V Q - S T V G V G UniRef90_B7GKK3_359_585 P F V F E R F Y K A D K A R T R G R S - G T G L G L A I A K N I V E A H K G T I T V H - S K L G E G UniRef90_C1DVW6_110_330 P L I F E R F Y R V D K S R S R N I G - G T G L G L S I V K H I T E A H K G K V W V E - S K L G E G UniRef90_C4L472_342_574 S R I F E R F Y R V D K A R S R N S G - G T G L G L A I V K H I I D L H H A T I D V E - S E E G K G UniRef90_D7GPR0_250_485 E R V F E R F Y R V D K A R S R E T G - G T G L G L A I T K S V V L M H H G A I R V D - S V E G E G UniRef90_B4S8R4_490_736 D K I F E K F Y R V E R P - G E E I E - G T G L G L P I V K E I I A A H K G S I E V N - S K K D F G UniRef90_A5GAH6_406_635 E R I F E R F Y R V N N T A C R V F G - G T G L G L A L V R E I V T A H G G E V W V E - S T L G K G UniRef90_C6WZH9_504_741 G K I F E R F Y R V S G D D E K T F P - G F G I G L Y I V K D I I Q R L D G K I W V E - S E K N Q G UniRef90_B0TGE0_245_473 P R I F E R F Y R V D K A R S R E L G - G T G L G L A I V K H I I E R S G G R V T V Q - S K V G V G UniRef90_D5E978_387_612 N M I F D P F I Q A D S S N T R K Y G - G T G L G L A L V K E Y V E M H G G T I W V E - S E L G K G UniRef90_F5LRU7_361_595 P R I F E R F Y R V D K A R S R S S G - G T G L G L S I V K H L V E M H H G T I R V E - S E V G Y G UniRef90_Q4A159_364_598 D K I F D R F Y R V D K A R T R K M G - G T G L G L A I S K E I V E A H N G R I W A N - S V E G Q G

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Electronic Supplementary Material (ESI) for Medicinal Chemistry Communications This journal is © The Royal Society of Chemistry 2013

Input_pdb_SEQRES_2C2A S R F F V W I P K D R A G E D N R Q D N - UniRef90_A5IIT0_236_493 S R F F V W I P K D R A G E D N R Q D N - UniRef90_B9KAB5_220_473 S R F F V W I P Y D H G T E D N R - - - - UniRef90_UPI000210F96E_244_482 S I F Y V ------UniRef90_B7IDY9_224_462 T T F E L V I P ------UniRef90_A6LN40_223_461 S I F R V N I P ------UniRef90_A8F6Z9_244_486 T V F Y V K I P Q ------UniRef90_A7HK36_224_466 T K F I V T L P K N ------UniRef90_D5WTD2_380_614 S R F F V Q F P R ------UniRef90_Q67RF9_205_438 S T F T V I L P ------UniRef90_B3E3A4_350_579 S T F T V T L P ------UniRef90_C1P968_353_593 S T F I V T L P R T Q T R P D ------UniRef90_UPI000210FB4E_174_410 T T F T V V L P ------UniRef90_D7AHN4_358_582 T T F ------UniRef90_D5X969_353_585 S K F T F Y L P ------UniRef90_D8PBL4_363_603 S R F V V H L P ------UniRef90_D7UVZ9_356_591 T T F S I H L P K T K ------UniRef90_C5D651_348_580 T T F T V H F P K ------UniRef90_F4BLP5_336_567 T T F I V R L P ------UniRef90_Q3MGM2_1112_1344 S N F Y F T L P ------UniRef90_B8G4S5_316_540 S R F L F T L P L S R ------UniRef90_E0FRK4_227_461 S V F T I E L P L K D R ------UniRef90_B1ZT44_154_390 A R F F F T L P E A E A ------UniRef90_C9RTX6_347_579 T V F T I H F P K ------UniRef90_A4XMJ6_338_561 T T F T V V L P ------UniRef90_UPI00018511C5_286_519 T T F I V K V S K E ------UniRef90_A5ILS8_180_410 T V M R V F L P K ------UniRef90_B9K7H6_180_412 T L M R V Y L P K G R ------UniRef90_F2I7J7_353_596 S T F T V Y L P K N ------UniRef90_B5YHW7_385_611 S R F G F S F P ------UniRef90_C0A490_167_399 A S F H F T L P ------UniRef90_D6XVE0_357_597 T T F S V F L P F S Q G E D ------UniRef90_A6CR52_338_570 T T F T V T L N K ------UniRef90_F5SLG1_353_585 T E I T L T F P R ------UniRef90_A4FWN1_406_639 S T F H I I L P I S V E G Q ------UniRef90_D3URW5_355_589 S T F R V T L P K ------UniRef90_E8R548_187_428 S R F T V R L P R Q R ------UniRef90_C9RD18_197_417 S R F W V Y L P S P Q ------UniRef90_C1PEW1_349_587 T T F S F F L P K ------UniRef90_Q1DCL6_267_509 S R F T I H L P A G K A ------UniRef90_A8F5W9_184_414 T S F T V K L P V E R ------UniRef90_Q2RFL3_239_485 S H F F F T L P I A A E E G G R S N Y Q E UniRef90_D1JAG2_243_467 S T F ------UniRef90_E5WJB7_351_584 T S F I I E L P K ------UniRef90_F6CIV3_222_456 S L F Y F T L P ------UniRef90_F6DKA0_218_449 S T F I F T L P ------UniRef90_E3Z246_18_252 S T F R V T L P K ------UniRef90_B5YHI6_153_383 T K V K I V I P ------UniRef90_A9GF59_268_496 T Q F T V R L A R ------UniRef90_E8WRA5_348_584 S V F S F T L P R A G D ------UniRef90_Q097K6_265_506 S L F T L Q L P A G K A ------UniRef90_E1KHP7_365_592 T E V I V R L P ------UniRef90_A9AVU3_644_869 T T F N V Q L P ------UniRef90_A6UWZ1_410_640 S T F H I L L P L D K ------UniRef90_D4Y401_348_580 T T F T V H F P K ------UniRef90_D7ATL0_341_566 T I V R V K L P ------UniRef90_Q1PXZ9_292_526 S T F Y F T I P ------UniRef90_E7M6U2_368_603 T T F N I E L P ------UniRef90_D7BCF8_586_818 T T F S L T L P ------UniRef90_D0MGH9_109_352 S T F A F R L P V A L A G R S ------UniRef90_UPI000212A698_523_767 S T F T F T I D T K R N Q E ------UniRef90_E1K386_410_648 S V F H I I I P ------UniRef90_B9M7U2_251_475 S T F F I S L P ------UniRef90_Q3AAG9_206_440 S A F G F T I P ------UniRef90_UPI0001E8932B_350_584 T A F T V K L S K E ------UniRef90_C4G960_243_473 T T F D V R I P ------UniRef90_C6J6K9_342_579 T T F I L E L P ------UniRef90_A0YQV3_1128_1360 S T F I V T L P ------

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Electronic Supplementary Material (ESI) for Medicinal Chemistry Communications This journal is © The Royal Society of Chemistry 2013

UniRef90_E3PT03_185_421 S K F I I E F P K N ------UniRef90_B7GGU1_348_587 T T F T V H F R A D A C A D E ------UniRef90_Q39S62_358_588 S E F W F T I K K ------UniRef90_B8D0H3_363_592 S L F R F Y L N K ------UniRef90_F5L948_225_461 S I F C V Y L Y Q K R ------UniRef90_E0NJE3_365_590 T K M T L R F P ------UniRef90_A7II27_682_911 A C F A F R L P ------UniRef90_B9DNB3_332_557 T T F ------UniRef90_A7HN49_181_412 T T F R V Y F K K ------UniRef90_E6QIY0_358_593 S R F L F T L P A G S T A I D S - - - - - UniRef90_F4L5H3_895_1123 S K F F F S L Q K ------UniRef90_A9AUY3_448_692 T T F W V T L P ------UniRef90_Q1IKU6_785_1018 S E F F I L L P R ------UniRef90_B5YD58_456_687 T T F T I R L P R ------UniRef90_UPI00016BFB3D_364_592 T ------UniRef90_E8SIU9_335_566 S R F K V V L P E ------UniRef90_B9E797_336_561 S T F ------UniRef90_Q8EPE4_222_453 T T I H I Y I P K ------UniRef90_D5DL55_355_590 T T F F I K L P K ------UniRef90_E0HX50_173_410 T I L K V K L P ------UniRef90_B8DZU7_455_686 T T F T I R L P R ------UniRef90_D6GSX7_369_596 T V F T I S L P ------UniRef90_D7CLL1_123_351 S T F G F S L W V ------UniRef90_Q6LXP6_406_633 S T F H I I L P ------UniRef90_Q67LR3_257_496 S T F S F T I P V E P G G ------UniRef90_A6LP23_177_414 T K F I V T L P ------UniRef90_B1HWE4_263_498 T T M I V M I P K N ------UniRef90_Q2B2H9_351_585 T T F K V Q L H R E ------UniRef90_B8FA30_356_583 A A F ------UniRef90_B5YJP0_360_619 S T F Y F T I P L K R K E E F N E N I N - UniRef90_F0JJT0_240_468 A T F R F T L P ------UniRef90_E1KHE7_585_832 S V F A V S L P ------UniRef90_C9LCS1_237_475 T T F S V R I P L N Y I G ------UniRef90_B7IEX9_176_421 T K F V V T L P I N R E E D N N - - - - - UniRef90_Q8TMU8_474_720 S V F G F S I P ------UniRef90_Q71Y67_354_593 S D F I I T L P ------UniRef90_D5DMV7_352_585 T T F S V K L H K ------UniRef90_A5D189_222_456 S T F S F V I P ------UniRef90_C0Z7X8_357_585 T T F T V T L P ------UniRef90_D4TMU3_804_1043 S S F Y F T L P ------UniRef90_Q0W6Q5_299_531 S T F F I S L P K ------UniRef90_B9E6M6_350_585 T T F V I S I P K V D D T K N N K - - - - UniRef90_UPI000212C3B1_361_596 T K F I I E M P ------UniRef90_A6UPU7_401_631 S T F H I V L P ------UniRef90_A5UQE0_447_687 S T F Y F T L P ------UniRef90_A1HSJ7_400_654 S R F T F V L P V R Q D G ------UniRef90_F2JII5_342_577 T K V I L N F P E ------UniRef90_Q8R6U6_339_575 T V V T V Q L P Y S K ------UniRef90_Q8PT37_279_503 S T F T F E V P ------UniRef90_D8G5S6_939_1165 S I F Y F M I P ------UniRef90_A8FJB5_372_608 T T V T F T L P Y N E E Q E D D - - - - - UniRef90_A5ITL6_318_551 S T F K V I L K D ------UniRef90_F6B3A9_217_450 S T F S F T L P ------UniRef90_D9QVY1_356_592 T K F I F W L P K P K ------UniRef90_A9AA11_406_633 S T F H I I L P ------UniRef90_D5E8Z5_365_588 S T F ------UniRef90_D2QCT5_672_903 A E F T C S L P ------UniRef90_A3DHV5_362_596 T E V T V K L P ------UniRef90_B0ADS6_194_431 S D F I V T I P V D ------UniRef90_E7RC70_372_606 T S I F F T L P F E E D D G G E - - - - - UniRef90_A0B593_141_369 S T F Y F T L P ------UniRef90_D4IVS0_239_469 T T F D V R I P ------UniRef90_B1YMQ3_615_835 S T F T I R F P ------UniRef90_C1F3B6_554_791 S S F F F T V A R N V A ------UniRef90_E7RJV0_231_462 T T F T I Y L P ------UniRef90_D3UPQ2_354_596 S D F I I T L P L E K ------UniRef90_E0RD24_357_594 T T F T V E L P ------UniRef90_F4LRR4_346_580 T S F T V Y I P K ------UniRef90_Q7NDS1_97_331 S T F T V S L P A V Q A G ------UniRef90_Q647M8_182_410 S T F Y F V I P ------UniRef90_B8G6G1_479_712 S S F S F T L P ------UniRef90_B7GKK3_359_585 T T F T F T L P ------UniRef90_C1DVW6_110_330 S K F F I K I P ------UniRef90_C4L472_342_574 T T F T I T F P R ------UniRef90_D7GPR0_250_485 S T F M V R I P ------UniRef90_B4S8R4_490_736 S T F F V R L P L S T S G ------UniRef90_A5GAH6_406_635 S T F F V S L P ------UniRef90_C6WZH9_504_741 S K F Y F S L P ------UniRef90_B0TGE0_245_473 S T F T V T F P ------UniRef90_D5E978_387_612 S T F T F T I P ------UniRef90_F5LRU7_361_595 T E F I I E L P ------UniRef90_Q4A159_364_598 T S I F I T L P ------S24

Electronic Supplementary Material (ESI) for Medicinal Chemistry Communications This journal is © The Royal Society of Chemistry 2013

Fig. S6 Competition of HK853 activity in the presence of guanidine derivatives 48 and 49. Each lane contains 90 ng HK853 (A) Increasing concentrations of 48 competed with B-ATPγS only at concentrations greater than 800 µM (B) Increasing concentrations of 49 competed steadily with B- ATPγS.

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Fig. S7 Rescue of HK853 activity in the presence of inhibitory concentrations of compounds 3, 48 and 49. Each lane contains 97 ng HK853. (A) A constant concentration of compound 48 (800 µM) does not show competitive effects on B-ATPγS activity-based labeling of HK853. The defects in lanes 2-4 are due to a deformity in the gel (B) A constant concentration of compound 49 (800 µM) prevents approximately 60% B-ATPγS labeling of HK853. The difference between lanes 1 and 8 illustrates the effects of 49 on the ability of HK853 to autothiophosphorylate. (C) NH125 (3) is marketed as an HK inhibitor, and inhibition of HK autophosphorylation was shown in previous studies19. A constant concentration of NH125 (3) (800 µM) prevents approximately 60% B-ATPγS labeling of HK853. The difference between lanes 1 and 8 illustrates the effects of NH125 (3) on the ability of HK853 to autothiophosphorylate.

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Fig. S8 Aggregation analysis of HK853 in the presence of compounds 3, 48 and 49. (A) Native-PAGE shows that HK853 aggregates in the presence of greater than 100 µM of compound 48. 95 ng of HK853 was loaded in each lane. (B) Crosslinking experiments also show 48 causes aggregation at concentrations greater than 100 µM. 85 ng HK853 was loaded per lane. The addition of Triton X-100 prevents 48- induced aggregation (C) Native-PAGE shows that HK853 aggregates in the presence ~50 µM 49. 95 ng of HK853 was loaded in each lane. (D) Crosslinking experiments also show that 49 causes aggregation at concentrations of approximately 50 µM. 85 ng HK853 was loaded per lane. The addition of Triton X-100 prevents 49-induced aggregation. (E) Native-PAGE shows that HK853 aggregates in the presence of 50-

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100 µM NH125 (3). 95 ng of HK853 was loaded in each lane. The addition of Triton X-100 prevents NH125 (3)-induced aggregation (F) Crosslinking experiments also show that NH125 (3) causes aggregation at concentrations greater than 10 µM. 85 ng HK853 was loaded per lane. The addition of Triton X-100 prevents NH125 (3)-induced aggregation.

Fig. S9 Triton X-100 restoration of HK853 activity labeling. Since NH125 (3) was proposed to be a nonspecific colloidal aggregator20, Triton X-100 was added to prevent NH 125-induced aggregation. As judged by coomassie staining, there is even loading of protein in lanes 3 and 4. Lane 3 in the fluorescence gel shows a drastic decrease in activity-based labeling; however, restoration of labeling was demonstrated when detergent was added in lane 4. This supports that the mechanism of HK inhibition by NH125 (3) is through aggregation. Additionally, Triton X-100 was used in aggregation experiments to restore HK853 to native oligomeric states. 90 ng HK853 was loaded per lane.

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Fig. S10 Competition and rescue of HK853 activity in the presence of compound 50 (A) Increasing concentrations of fragment 50 did not show competition with B-ATPγS. Each lane contains 90 ng HK853. The irregular band shapes in lanes 2 and 3 are due to a deformity in the gel. (B) A constant concentration of fragment 50 (800 µM) has no effect on B-ATPγS activity-based labeling of HK853. 97 ng of HK853 was loaded in each lane.

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Fig. S11. Analysis of guanidine for HK853 aggregation and competition with activity-based probe. Since guanidinium salts can be used to denature proteins, we wanted to be sure that the guanidine group was not causing denaturation, thus decreasing the activity of HK853. The molar ratio of guanidine:guanidine-HCl is ~0.6:1. Guanidine-HCl was used to prepare known concentrations of guanidine, and the final pH was 8.5. (A) Native-PAGE shows that guanidine does not cause aggregation at concentrations as high as 2 mM. 85 ng HK853 was loaded per lane. (B) Increasing concentrations of guanidine were not shown to affect the autothiophosphorylation of HK853, ensuring that decreases in labeling in activity-based experiments were not due to guanidine-induced denaturation. Each lane contains 90 ng HK853. The irregular band shapes in lanes 2-4 are due to a deformity in the gel.

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Fig. S12. Aggregation analysis of HK853 in the presence of the fragment 50. (A) Native-PAGE shows that HK853 does not aggregate in the presence of the fragment 50. 95 ng of HK853 was loaded in each lane. (B) Crosslinking experiments also show that the fragment 50 does not cause aggregation. 85 ng HK853 was loaded per lane.

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Fig. S13 Competition of HK853 activity in the presence of guanidine fragments 50 and 51. Each lane contains 90 ng HK853 (A) Increasing concentrations of 50 competed with B-ATPγS (B) Increasing concentrations of 51 competed with B-ATPγS.

Table S2. Competitive ABPP using 2 µM B-ATPγS (probe) and increasing concentrations of 51 (competitor) with HK853. Bands correlate to Fig. S13 B.

Integrated Density of Band 51 (mM) Fluorescence (AU) 0.00 271.17 0.05 205.95 0.10 177.52 0.20 216.84 0.40 188.02 0.60 221.99 0.80 212.36 1.00 186.24 2.00 200.62 3.00 188.26 4.00 165.37 5.00 162.81 6.00 139.09 7.00 103.35 10.00 86.01

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Figure S14. Aggregation analysis of HK853 in the presence of the modified fragment 51. (A) Native- PAGE shows that HK853 aggregates slightly at concentrations between 4 and 8 mM of 51. 95 ng of HK853 was loaded in each lane. (B) Crosslinking experiments also show that compound 51 causes subtle aggregation at concentrations in the low micromolar range only. 85 ng HK853 was loaded per lane.

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Docking-Based Virtual Screening General

All molecular modeling operations were performed using SYBYL X2.0 on a quad-core Intel Core i3

workstation operating at 3.06 GHz equipped with 4 GB 1333MHz DDR 3 RAM. Visualization of docked

poses was accomplished using the latest available release of UCSF Chimera.

Docking of Compounds.

The active sites of all receptors were defined based on the coordinates of the co-crystallized ligand and

the Protomol Generation Mode in Surflex using default settings. A portion of the co-crystallized ligand

was retained and used as a guide for the placement of compounds into the active site during docking. The

Surflex-Dock parameters were configured as follows:

Max Conformations per Fragment: 10

Max Number of Rotatable Bonds per molecule: 50

Activated: Consider Ring Flexibility

Density of Search: 6.00

Maximum Number of Poses per Ligand: 10

Minimum RMSD Between Final Poses: 0.5

All other parameter were kept at their default values

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In Vitro Activity Assays

General Methods and Information

Reagents were obtained from J.T. Baker, Mallinkrodt, Sigma, IBI, VWR, EMD Biosciences, Bio-Rad and

3 Fisher. BODIPY-FL-ATPγS was purchased from Invitrogen, NH125 from Tocris Bioscience, and BS -d0

from Thermo Scientific.

Experimental Methods

HK853 Construct (Thermotoga maritima)

The HK853 histidine kinase protein construct was generated as described previously21

PCR Site-Directed Mutagenesis for Generation of HK853 D411A Construct22

The DNA synthesized for wild-type HK853 was used as a template. Sense and antisense primers that

originally coded for D411 were altered to alanine (See Table S3). Primers were ordered from New

England Biolabs. Two reactions were prepared in PCR tubes: 2.5 ng HK853 wild-type DNA template, 2.5

µL 2.5 mM dNTPs, 2.5 µL 10 X Pfu buffer, 14.65 µL nuclease-free water, and 0.25 µL 100 X Pfu. To

one tube, 2.5 µL of 5 µM mutant sense primer (FHJ088) and 2.5 µ L of 5 µ M outermost wild-type

antisense primer were added. To the other, 2.5 µL of 5 µM outermost wild-type sense primer and 2.5 µL

of mutant antisense primer (FHJ089) were added. The final reaction volumes were 25 µL. The PCR

reaction was 95°C for 60 s; 30 cycles of 95°C for 30 s, 56°C for 120 s, and 72°C for 90 s; and 72°C for

360 s. To amplify the mutated template, 0.5 µL of product from both the first and second tubes were

mixed with 5.0 µL 2.5 mM dNTPs, 5.0 µL of 5 µM outermost sense primer, 5.0 µL of 5 µM outermost

antisense primer, 5.0 µL of 10 X Pfu buffer, 28.5 µL nuclease-free water, and 0.5 µL 100 X Pfu to a total

volume of 50 µL. The same PCR method was run. PCR product was purified, digested, and ligated into

the p-His-parallel vector as before.23 The DNA sequence was confirmed as successful through sequencing

at the Indiana Molecular Biology Institute. Additionally, transformation of p-His-parallel-HK853 D411A

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into E. coli strain BL21 (DE3)Rosetta, pLysS, and subsequent protein overexpression and purification

were performed as described previously21. Overexpressed mutant protein is shown in Fig. S15, and the

final protein properties are shown in Table S4.

Table S3. Mutant primers used in PCR site-directed mutagenesis to generate HK853 D411A

Primer Sequence Comments Wild-type, sense, KEW026 TGAGAAAGACGGTGGTGTGCTGATCATCGTGGAGGATAATG Asp Wild-type, KEW027 GGTCCGGGATGCCGATACCATTATCCTCCACGATGATCAG antisense, Asp FHJ088 TGAGAAAGACGGTGGTGTGCTGATCATCGTGGAGGCGAATG Mutant, sense, Ala Mutant, antisense, FHJ089 GGTCCGGGATGCCGATACCATTCGCCTCCACGATGATCAG Ala

Figure S15. HK853 D411A overexpression. The protein ladder is on the left, non-induced E. coli lysate is in lanes 1 and 2 (two separate cultures), and induced E. coli lysate is in lanes 3 and 4 (two separate induced cultures).

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Table S4. Final protein properties of the HK853 D411A mutant. Gray residues represent a polyhistidine tag coded by the p-His-parallel vector. The red residue is the mutated alanine. Values for pI and extinction coefficient are estimated.

Circular Dichroism (CD) Spectroscopy of HK853 Proteins

Previous CD methods were used as guidelines for this procedure.24, 25 Using a Jasco J-715 CD

spectropolarimeter, CD spectra were acquired for purified HK853 wild-type and D411A proteins.

Proteins were exchanged into 10 mM potassium phosphate, pH 7.5, four times using 0.5-mL 10K Amicon

Ultra centrifugal filters (Millipore). The Bio-Rad DC Protein Assay was used to determine protein

concentrations, which were 0.111 mg/mL for HK853 wild-type and 0.110 mg/mL for HK853 D411A.

Buffer and protein solutions were filtered with 0.22-µm Ultrafree-MC centrifugal filters (Millipore) to

ensure the removal of any particulates that could interfere with CD readings. Protein solutions were

loaded into a 0.1-cm quartz cuvette (Hellma), and spectra were obtained at 25°C. Each spectrum was

measured in triplicate with the following parameters: standard (100 mdeg) sensitivity, 190-270 nm range,

0.5 nm data pitch, continuous scanning mode, scanning speed of 100 nm/min, response of 1 s, 1.0-nm

bandwidth, and an accumulation of 4 scans. Spectra were smoothed using a Savitsky-Golay filter (15-

point smoothing window). Averaged buffer spectra were subtracted from the protein spectra. The CD data

in millidegrees were used to calculate mean residue ellipticity, [θ], according to the following equation:

[θ]= (millidegrees)/(path length in mm x concentration in M x number of amino acid residues).25 The final

units for mean residue ellipticity were deg cm-1 dmol-1. Additionally, data from each CD spectrum (in

millidegrees) were submitted to Dichroweb for secondary structure analysis using SELCON3 and

reference set 4.26-28 Values for helices, strands, and turns from each spectrum were averaged, and error

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was reported as the standard deviation. NRMSD values for Dichroweb results ranged from 0.037 to

0.052.

Fig. S16 CD spectra of HK853 wild-type (pink) and D411A (purple) proteins scanned from 190-270 nm shown as mean residue ellipticity.

Table S5 Estimated secondary structure of HK853 proteins (n=3)

Construct % α-helix % β-sheet % turn HK853 wild-type 42.1 ± 0.3 14.7 ± 0.3 16.6 ± 0.1 HK853 D411A 44.3 ± 0.5 14.1 ± 0.4 16.6 ± 0.3

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Rescue ABPP analysis of NH125 (3), 48, 49, 50 and 51

All analogues except AMP-PNP were dissolved in DMSO, and the final DMSO concentration per sample

was no greater than 5% (v/v) as stated previously.

Purified HK853 (0.4 µM) in reaction buffer was incubated with a constant concentration (600 or 800 µM)

of analogue for 30 min. Individual samples were mixed with 1 µL increasing concentrations of B-ATPγS

(0.1-15 µM final concentration) and incubated at RT for 1 h in the dark to prevent fluorophore

photobleaching. After incubation, reactions were quenched with 2X SDS-PAGE loading buffer. Samples

were not heated before running on SDS-PAGE gels. After analyzing gels by fluorescence, they were

coomassie stained.

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Saturation Transfer Differential NMR Experiments

All NMR spectra were acquired at 298 K on a Varian DDR 600 MHz spectrometer operating at 599.8

MHz or a Varian DDR 800 MHz spectrometer operating at 799 MHz for 1H, both equipped with a 5mm

triple resonance inverse detection probe with z-axis gradient. Saturation transfer difference (STD) spectra

were acquired using a standard Varian STD pulse sequence that subtracts NOE spectra from reference

spectra during the experiment.29 Saturation transfer time was 2 s using a 47 ms Gaussian pulse. Irradiation

was alternated between 0.73 ppm and 30.2 ppm for the NOE and reference portions, respectively.

Sample preparation

Ligand stocks were made with DMSO-d6 and phosphate buffers were prepared in D2O.

Unless otherwise noted, each sample tube contained 5 mM ligand + 0.25 mM protein (20:1 excess of

ligand to protein) + 75 mM phosphate buffer in a 500 µL total volume D2O.

Determination of Kd Using STD-NMR

The approach of Angulo et al. was used to construct the binding isotherms of compounds 50 and 51 to

HK853 using the initial growth rates approach (Tables S5 and S6).11 A variant of the STD-NMR

sequence was utilized for selective saturation and the acquisition of on- and-off resonance spectra30.

Values of 0.73 ppm and 30.2 ppm were used for on- and off resonance frequencies, respectively. To

construct the STD buildup curves (Figs. S17 and S18), stock solutions of compounds 50 and 51 in DMSO

were titrated (DMSO did not exceed 1% v/v) into a sample of 0.53 µM HK853 in 500 µL D2O and

spectra were acquired at 25 ºC using an array of saturation times of 1, 2, 3 and 4 s. The concentrations of

compounds 50 and 51 ranged from 0.6 – 4 mM and the samples were allowed to equilibrate for 15 min

between titrations. Plotting the initial slopes and fitting to a Langmuir isotherm yielded the

31 thermodynamic Kd values of 50 and 51. Data were based on the aromatic protons of 50 (6.80-6.84 ppm)

and 51 (7.85-7.90 ppm) and processed using MestreNova 6.02.

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Table S5 Initial slopes of the STD build up curves for compound 50 -1 Ligand concentration STD-AFmax Ksat (s ) STD-AF0 (mM) 0.6 184.56 0.68 124.50

0.8 229.83 0.58 132.45

1 307.37 0.44 135.41

2 587.79 0.42 244.66

4 1431 0.23 329.13

1000

0.6 mM

800 0.8 mM y = m1*(1-exp(-1*m2*x)) 1.0 mM y = m1*(1-exp(-1*m2*x))Value Error m1 184.56 38.974 2.0 mM Value Error 600 m2 0.6746 0.37675 m1 229.83 11.586 4.0 mM Chisq 1274.7 NA m2 0.57631 0.068681 y = m1*(1-exp(-1*m2*x))y = m1*(1-exp(-1*m2*x)) y = m1*(1-exp(-1*m2*x))2 0.6584 NA ChisqR 71.525 NA Value Error Value Error 2 Value Error 400 R 0.9895 NA m1 587.79 m148.2 307.37 45.058 m1 1431 585.73 STD-AF[a.u.] m2 0.41624 0.065575m2 0.44053 0.12829 m2 0.23128 0.13813 Chisq 434.69 ChisqNA 459.74 NA Chisq 7828.5 NA 2 200 R 0.99075 NA2 0.96022 NA 2 R R 0.96182 NA

0 0 1 2 3 4 5 Saturation time [s] Figure S17. STD-Buildup curves of compound 50’s binding to HK853.

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Table S6 Initial slopes of the STD build up curves for compound 51 -1 Ligand concentration STD-AFmax Ksat (s ) STD-AF0 (mM) 0.6 156.17 0.35 53.97

0.8 158.55 0.42 67.25

1 187.77 0.37 69.81

2 327.32 0.25 82.41

3 394.31 0.24 94.37

250 0.6 mM 0.8 mM 1 mM 200 2 mM 3 mM 150

100 STD-AF [a.u.] STD-AF

50

0 0 1 2 3 4 5 Saturation time [s]

y = m1*(1-exp(-1*m2*x)) y = m1*(1-exp(-1*m2*x)) y = m1*(1-exp(-1*m2*x)) y = m1*(1-exp(-1*m2*x))Figure S18. STD-Buildup curves of compound 51’s binding to HK853. y = m1*(1-exp(-1*m2*x)) Value Error Value Error Value Error Value Error Value Error m1 156.17 8.4038 m1 158.55 15.701 m1 187.77 20.189 m1 327.32 35.256 m1 394.31 128.88 m2 0.34557 0.032292 m2 0.42414 0.081584 m2 0.37179 0.072116 m2 0.25177 0.040858 m2 0.23932 0.11558 Chisq 6.9371 NA Chisq 49.155 NA Chisq 51.736 NA Chisq 38.846 NA Chisq 430.32 NA 2 2 0.98598 NA 2 0.98831 NA 2 2 0.96918 NA R 0.99765 NA R R R 0.99636 NA R S42

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Measurement of STD Amplification Factors

32 The STD spectra were quantitatively analyzed by calculation of the STD amplification factors fSTD of

the averaged aromatic regions of a single sample containing 1 mM tyramine, ADP, 50 and 51 and 0.53

µM HK853 in 500 µL D2O. Peak processing was performed using VNMRJ.

References

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