2Qtl Lichtarge Lab 2006

Pages 1–8 2qtl Evolutionary trace report by report maker June 23, 2010 4.3.1 Alistat 7 4.3.2 CE 7 4.3.3 DSSP 7 4.3.4 HSSP 8 4.3.5 LaTex 8 4.3.6 Muscle 8 4.3.7 Pymol 8 4.4 Note about ET Viewer 8 4.5 Citing this work 8 4.6 About report maker 8 4.7 Attachments 8 1 INTRODUCTION From the original Protein Data Bank entry (PDB id 2qtl): Title: Crystal structure of the fad-containing fnr-like module of human methionine synthase reductase Compound: Mol id: 1; molecule: methionine synthase reductase; CONTENTS chain: a; fragment: fnr-like module; synonym: methionine synthase reductase, mitochondrial; msr; ec: 1.16.1.8; engineered: yes; 1 Introduction 1 mutation: yes Organism, scientific name: Homo Sapiens; 2 Chain 2qtlA 1 2qtl contains a single unique chain 2qtlA (448 residues long). 2.1 Q7Z4M8 overview 1 2.2 Multiple sequence alignment for 2qtlA 1 2.3 Residue ranking in 2qtlA 1 2.4 Top ranking residues in 2qtlA and their position on the structure 1 2 CHAIN 2QTLA 2.4.1 Clustering of residues at 25% coverage. 2 2.4.2 Overlap with known functional surfaces at 2.1 Q7Z4M8 overview 25% coverage. 2 From SwissProt, id Q7Z4M8, 84% identical to 2qtlA: 2.4.3 Possible novel functional surfaces at 25% Description: MTRR protein (Fragment). coverage. 4 Organism, scientific name: Homo sapiens (Human). Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; 3 Notes on using trace results 6 Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; 3.1 Coverage 6 Catarrhini; Hominidae; Homo. 3.2 Known substitutions 6 3.3 Surface 6 3.4 Number of contacts 7 3.5 Annotation 7 2.2 Multiple sequence alignment for 2qtlA 3.6 Mutation suggestions 7 For the chain 2qtlA, the alignment 2qtlA.msf (attached) with 111 sequences was used. The alignment was assembled through combi- 4 Appendix 7 nation of BLAST searching on the UniProt database and alignment 4.1 File formats 7 using Muscle program. It can be found in the attachment to this 4.2 Color schemes used 7 report, under the name of 2qtlA.msf. Its statistics, from the alistat 4.3 Credits 7 program are the following: 1 Lichtarge lab 2006 2.4 Top ranking residues in 2qtlA and their position on the structure In the following we consider residues ranking among top 25% of residues in the protein . Figure 3 shows residues in 2qtlA colored by their importance: bright red and yellow indicate more conserved/important residues (see Appendix for the coloring scheme). A Pymol script for producing this figure can be found in the attachment. Fig. 1. Residues 217-454 in 2qtlA colored by their relative importance. (See Appendix, Fig.7, for the coloring scheme.) Fig. 2. Residues 455-698 in 2qtlA colored by their relative importance. (See Appendix, Fig.7, for the coloring scheme.) Fig. 3. Residues in 2qtlA, colored by their relative importance. Clockwise: front, back, top and bottom views. Format: MSF Number of sequences: 111 2.4.1 Clustering of residues at 25% coverage. Fig. 4 shows the Total number of residues: 46026 top 25% of all residues, this time colored according to clusters they Smallest: 369 belong to. The clusters in Fig.4 are composed of the residues listed Largest: 448 in Table 1. Average length: 414.6 Table 1. Alignment length: 448 Average identity: 34% cluster size member Most related pair: 99% color residues Most unrelated pair: 17% red 97 283,284,285,291,293,294,295 Most distant seq: 38% 297,307,309,310,311,312,314 319,324,370,375,426,428,448 450,451,452,453,454,455,456 Furthermore, 1% of residues show as conserved in this alignment. 457,458,467,469,470,471,473 The alignment consists of 66% eukaryotic ( 18% vertebrata, 485,487,488,489,490,525,530 6% arthropoda, 18% fungi, 13% plantae), and 32% prokaryotic 532,533,541,542,544,545,546 sequences. (Descriptions of some sequences were not readily availa- 547,548,550,551,552,553,554 ble.) The file containing the sequence descriptions can be found in 555,558,559,572,576,577,578 the attachment, under the name 2qtlA.descr. 579,580,581,586,588,589,592 593,608,609,610,611,622,624 2.3 Residue ranking in 2qtlA 625,626,627,648,649,650,651 652,653,656,657,659,660,664 The 2qtlA sequence is shown in Figs. 1–2, with each residue colored according to its estimated importance. The full listing of residues continued in next column in 2qtlA can be found in the file called 2qtlA.ranks sorted in the attachment. 2 Table 2. continued res type subst’s cvg noc/ dist (%) bb (A˚ ) 652 D D(86) 0.06 1/0 4.79 P(9) G(1)SN 697 W Y(33) 0.06 126/20 3.34 W(48) F(18) 696 I V(79) 0.07 3/3 4.38 I(18) T(1) 547 T T(96) 0.08 3/0 4.47 S(2)A 490 T S(71) 0.09 22/7 2.64 T(28) 375 E E(42) 0.11 1/0 4.97 D(54) S(1)N 312 A A(31) 0.12 3/0 4.14 H(57) C(4) Fig. 4. Residues in 2qtlA, colored according to the cluster they belong to: T(1) red, followed by blue and yellow are the largest clusters (see Appendix for S(3)V the coloring scheme). Clockwise: front, back, top and bottom views. The 473 V V(81) 0.13 18/1 3.71 corresponding Pymol script is attached. L(8) E(7)A M(1) Table 1. continued 525 R E(10) 0.13 4/0 3.44 cluster size member R(62) color residues K(17) 667,691,692,695,696,697 Q(7) blue 9 380,382,385,388,392,401,404 H(2) 413,433 452 P L(18) 0.16 58/34 2.61 P(7) Table 1. Clusters of top ranking residues in 2qtlA. F(9) Y(47) E(12) 2.4.2 Overlap with known functional surfaces at 25% coverage. H(1)MAS The name of the ligand is composed of the source PDB identifier 469 V T(73) 0.16 11/11 2.85 and the heteroatom name used in that file. V(2) FAD binding site. Table 2 lists the top 25% of residues at the inter- I(4) face with 2qtlAFAD700 (fad). The following table (Table 3) suggests C(6) possible disruptive replacements for these residues (see Section 3.6). L(9) Table 2. M(1)AS res type subst’s cvg noc/ dist 488 V G(9) 0.17 24/17 2.88 (%) bb (A˚ ) V(70)T 451 R R(100) 0.02 42/3 2.91 I(2) 454 S S(100) 0.02 23/12 2.81 H(3) 487 G G(100) 0.02 21/21 3.26 L(6) 695 D D(88) 0.02 6/0 3.85 Q(6) E(11) 489 C A(38) 0.20 16/12 2.76 550 A A(98) 0.04 2/0 4.74 C(54)N S(1) T(4)V 453 Y Y(97) 0.05 81/24 2.77 470 F V(47) 0.23 13/8 3.21 F(2) continued in next column continued in next column 3 Table 2. continued res type subst’s cvg noc/ dist (%) bb (A˚ ) F(3) C(13) A(13) S(1) I(15) Y(3)L 471 N G(30) 0.23 8/5 3.59 N(3) A(31) V(26) S(8) Table 2. The top 25% of residues in 2qtlA at the interface with FAD.(Field names: res: residue number in the PDB entry; type: amino acid type; substs: substitutions seen in the alignment; with the percentage of each type in the bracket; noc/bb: number of contacts with the ligand, with the number of contacts realized through backbone atoms given in the bracket; dist: distance of closest apporach to the ligand. ) Fig. 5. Residues in 2qtlA, at the interface with FAD, colored by their relative Table 3. importance. The ligand (FAD) is colored green. Atoms further than 30A˚ away res type disruptive from the geometric center of the ligand, as well as on the line of sight to the mutations ligand were removed. (See Appendix for the coloring scheme for the protein 451 R (TD)(SYEVCLAPIG)(FMW)(N) chain 2qtlA.) 454 S (KR)(FQMWH)(NYELPI)(D) 487 G (KER)(FQMWHD)(NYLPI)(SVA) 695 D (R)(FWH)(YVCAG)(K) 550 A (KR)(YE)(QH)(D) 453 Y (K)(Q)(EM)(NR) 652 D (R)(H)(FW)(Y) 697 W (K)(E)(Q)(D) 696 I (R)(Y)(H)(K) 547 T (KR)(QH)(FMW)(E) 490 T (KR)(FQMWH)(NELPI)(D) 375 E (FWH)(R)(Y)(VCAG) 312 A (K)(ER)(YQ)(D) 473 V (Y)(R)(KH)(E) Fig. 6. A possible active surface on the chain 2qtlA. The larger cluster it 525 R (T)(Y)(VCADG)(S) belongs to is shown in blue. 452 P (R)(Y)(T)(KH) 469 V (R)(KY)(E)(H) 488 V (R)(YE)(K)(H) The residues belonging to this surface ”patch” are listed in Table 489 C (R)(KE)(H)(Q) 4, while Table 5 suggests possible disruptive replacements for these 470 F (K)(E)(QR)(D) residues (see Section 3.6). 471 N (Y)(H)(R)(FEW) Table 4.

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