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Interaction of Shikimic Acid with Shikimate Kinase

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Interaction of Shikimic Acid with Shikimate Kinase BBRC Biochemical and Biophysical Research Communications 325 (2004) 10–17 www.elsevier.com/locate/ybbrc Interaction of shikimic acid with shikimate kinase Jose´ Henrique Pereiraa, Jaim Simo˜es de Oliveirab, Fernanda Canduria,c, Marcio Vinicius Bertacine Diasa,Ma´rio Se´rgio Palmac,d, Luiz Augusto Bassob, Walter Filgueira de Azevedo Jr.a,d,*, Dio´genes Santiago Santose,* a Department of Physics, UNESP, Sa˜o Jose´ do Rio Preto, SP 15054-000, Brazil b Rede Brasileira de Pesquisa em Tuberculose Grupo de Microbiologia Molecular e Funcional, Departamento de Biologia Molecular e Biotecnologia, UFRGS, Porto Alegre, RS 91501-970, Brazil c Center for Applied Toxinology, Institute Butantan, Sa˜o Paulo, SP 05503-900, Brazil d Laboratory of Structural Biology and Zoochemistry, CEIS/Department of Biology, Institute of Biosciences, UNESP, Rio Claro, SP 13506-900, Brazil e Centro de Pesquisa e Desenvolvimento em Biologia Molecular e Funcional, Pontifı´cia Universidade Cato´lica do Rio Grande do Sul, Porto Alegre, RS 90619-900, Brazil Received 24 September 2004 Available online 19 October 2004 Abstract The crystal structure of shikimate kinase from Mycobacterium tuberculosis (MtSK) complexed with MgADP and shikimic acid (shikimate) has been determined at 2.3 A˚ resolution, clearly revealing the amino acid residues involved in shikimate binding. In MtSK, the Glu61 strictly conserved in SK forms a hydrogen bond and salt-bridge with Arg58 and assists in positioning the guan- idinium group of Arg58 for shikimate binding. The carboxyl group of shikimate interacts with Arg58, Gly81, and Arg136, and hydroxyl groups with Asp34 and Gly80. The crystal structure of MtSK–MgADP–shikimate will provide crucial information for elucidation of the mechanism of SK-catalyzed reaction and for the development of a new generation of drugs against tuberculosis. Ó 2004 Elsevier Inc. All rights reserved. Keywords: Drug design; Mycobacterium tuberculosis; Shikimate kinase; Structure; Shikimic acid The shikimate kinase (SK; EC 2.7.1.71), the fifth en- tyrosine and tryptophan [4,5]. The physiological role of zyme of the pathway, catalyzes the specific phosphoryla- SK I in E. coli is not clear. Since mutations in SK I are tion of the 3-hydroxyl group of shikimic acid using ATP associated with sensitivity to the antibiotic mecillinam as a co-substrate. In Escherichia coli, the SK reaction is [6] it has been suggested that SK I may have an alterna- catalyzed by two isoforms SK I encoded by the aroK tive biological role in which it phosphorylates shikimate gene [1] and SK II encoded by the aroL gene [2]. The only fortuitously [3]. Contrary to the presence of isoen- major difference between the isoenzymes is their Km zymes in E. coli, complete genome sequences of a num- for shikimate, 0.2 mM for the SK II and 20 mM for ber of bacteria, for example, Haemophilus influenzae and the SK I enzyme [3]. The SK II isoform appears to play Mycobacterium tuberculosis, have revealed the presence a dominant role in the shikimate pathway, its expression of only one SK-coding gene. Most of these SKs appear is controlled by the tyrR regulator, and it is repressed by to be encoded by aroK rather than aroL because their amino acid sequences have higher degree of identity with E. coli SK I. The kinetic parameters for aroK-encoded * Corresponding authors. MtSK are more similar to those of aroL-encoded E. coli E-mail addresses: [email protected] (W.F. de Azevedo SK II than to those of aroK-encoded E. coli SK I. The Jr.), [email protected] (D.S. Santos). MtSK Km value (0.41 mM) for shikimate suggests that 0006-291X/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2004.09.217 J.H. Pereira et al. / Biochemical and Biophysical Research Communications 325 (2004) 10–17 11 not all aroK-encoded SKs have high Km values for shi- Materials and methods kimate [7]. The three crystal structures of SK from Erwinia Crystallization. The MtSK was concentrated and dialyzed against chrysanthemi (EcSK) [8,9], which is encoded by aroL, 50 mM Na Hepes buffer, pH 7.5, containing 0.5 M NaCl and 5.0 mM MgCl2. This protein solution was mixed with 13.0 mM shikimate and show that SK belongs to the same structural family 13.0 mM ADP, and centrifuged prior to crystallization. The protein of nucleoside monophosphate (NMP) kinases for concentration was about 17.0 mgmLÀ1. The crystals were obtained by which structures are known for adenylate kinase the hanging-drop vapor-diffusion method. The well solution contained (AK) [10,11], guanylate kinase [12], uridylate kinase 0.1 M Na Hepes buffer, pH 7.5, 10% 2-propanol, and 35% PEG 3350, [13], and thymidine kinase [14]. The NMP kinases are and the drop was a mixture of 1.0 lL well solution and 1.5 lL of the protein solution. composed of three domains: CORE, LID, and NMP- Data collection and processing. The data set of MtSK–shikimate binding (NMPB) domains [15]. A characteristic feature was collected at a wavelength of 1.431 A˚ using the Synchrotron of the NMP kinases is that they undergo large confor- Radiation Source (Station PCr, LNLS, Campinas-Brazil) [21] and a mational changes during catalysis, for which AK is the CCD detector (MARCCD). The cryoprotectant contained 15% glyc- most extensively studied [15]. There are two flexible re- erol, 12% PEG 3350, and 3.5% propanol. The crystal was flash-frozen at 104 K under cold nitrogen stream generated and maintained with an gions of the structures that are responsible for move- Oxford Cryosystem. The oscillation range used was 1.0°, crystal to ment: one is the NMP-binding site which is formed detector distance was 90 mm, and the exposure time was 50 s. The data by a series helices between strands 2 and 3 of parallel set containing 160 frames was collected and processed to 2.3 A˚ reso- b-sheet and the other is the LID domain, a region of lution using the program MOSFLM [22] and scaled with SCALA [23]. varied size and structure following the fourth b-strand Molecular replacement and crystallographic refinement. The crystal structure of the MtSK–MgADP–shikimate was determined by stan- of the sheet [16,17,28]. In SK, the shikimate-binding dard molecular replacement methods using the program AMoRe [24], (SB) domain corresponds to the NMPB domain of using as search model the structure of MtSK–MgADP (PDB access NMP kinases. code: 1L4Y) [7]. After translation function computation the cor- Three functional motifs of nucleotide-binding en- relation was 65% and the Rfactor 38.3%. The highest magnitude of zymes are recognizable in MtSK, including a Walker correlation coefficient function was obtained for the Euler angles a = 54.85°, b = 85.32°, and c = 91.90°. The fractional coordinates are A-motif, a Walker B-motif, and an adenine-binding Tx = 0.7336, Ty = 0.5326, and Tz = 0.2768. The atomic positions loop. The Walker A-motif is located between the first obtained from molecular replacement were used to initiate the crys- b-strand (b1) and first a-helix (a1), containing the tallographic refinement. Structure refinement was performed using GXXXXGKT/S conserved sequence [18], where X X-PLOR [25]. In the following rigid-body refinement, the Rfactor represents any residue. This motif forms the phos- decreased from 38.3% to 35.8%. Further refinement continued with simulated annealing using the slow-cooling protocol, followed by phate-binding loop (P-loop), a giant anion hole which alternate cycles of positional refinement and manual rebuilding using accommodates the b-phosphate of the ADP by donat- XtalView [26]. Finally, the positions of waters, MgADP, and shikimate ing hydrogen bonds from several backbone amides were checked and corrected in Fobs À Fcalc maps. The final model has [19]. In addition to the Walker A-motif, a second con- an Rfactor of 20.7% and an Rfree of 28.7%. served sequence ZZDXXG called Walker B-motif [18] Root-mean-square deviation differences from ideal geometries for bond lengths, angles, and dihedrals were calculated with X-PLOR [25]. is observed, where Z represents a hydrophobic residue. The overall stereochemical quality of the final model for MtSK– An Asp-Ser replacement exists in MtSK. More re- MgADP–shikimate was assessed by the program PROCHECK [27]. cently, however, sequence and structural comparisons Atomic models were superposed using the program LSQKAB from for all P-loop-fold proteins classified shikimate kinase CCP4 [23]. The molecular surface areas have been calculated using the in the DxD group of enzymes [20], which has a con- program Swiss-PDBViewer v3.7 (www.expasy.org/spdbv), probe ra- dius of 1.4 A˚ , and a fixed radius for all atoms. served DxD motif in strand 2. The Walker B motif consensus in shikimate kinases is ZZZTGGG and the second glycine (Gly80 in MtSK) has been impli- cated in hydrogen bonding to the c-phosphate of Results and discussion ATP. The Walker B-motif provides a bond for the octahedral coordination of a Mg2+ cation, which, in The crystals of MtSK–MgADP–shikimate were turn, is coordinated to the b-andc-phosphate groups grown in the presence of 5.0 mM MgCl2, 13.0 mM of nucleoside triphosphates [18]. The adenine-binding ADP, and 13.0 mM shikimate. The data set of MtSK– loop motif may be described as a sequence stretch MgADP–shikimate was collected at 2.3 A˚ (Table 1) of I/VDXXX(X)XP [7]. This motif forms a loop that using the Synchrotron Radiation Source [21], and the wraps around the adenine moiety of ATP, connecting structure was solved by molecular replacement.
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