3RV6

Structure of a M. tuberculosis Salicylate Synthase, MbtI, in Complex with an Inhibitor with Phenyl R-Group

3RV6 の概要

• エントリーDOI: 10.2210/pdb3rv6/pdb
• 関連するPDBエントリー: 3RV7 3RV8 3RV9
• 分子名称: Isochorismate synthase/isochorismate-pyruvate lyase mbtI, 3-{[(E)-1-carboxy-2-phenylethenyl]oxy}-2-hydroxybenzoic acid, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: structural genomics, tb structural genomics consortium, tbsgc, salicylate synthase, chorismate binding, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 99204.33

構造登録者

Chi, G.,Bulloch, E.M.M.,Manos-Turvey, A.,Payne, R.J.,Lott, J.S.,TB Structural Genomics Consortium (TBSGC) (登録日: 2011-05-06, 公開日: 2012-05-09, 最終更新日: 2024-03-20)

主引用文献

Chi, G.,Manos-Turvey, A.,O'Connor, P.D.,Johnston, J.M.,Evans, G.L.,Baker, E.N.,Payne, R.J.,Lott, J.S.,Bulloch, E.M.
Implications of binding mode and active site flexibility for inhibitor potency against the salicylate synthase from Mycobacterium tuberculosis
Biochemistry, 51:4868-4879, 2012

PubMed Abstract: MbtI is the salicylate synthase that catalyzes the first committed step in the synthesis of the iron chelating compound mycobactin in Mycobacterium tuberculosis. We previously developed a series of aromatic inhibitors against MbtI based on the reaction intermediate for this enzyme, isochorismate. The most potent of these inhibitors had hydrophobic substituents, ranging in size from a methyl to a phenyl group, appended to the terminal alkene of the enolpyruvyl group. These compounds exhibited low micromolar inhibition constants against MbtI and were at least an order of magnitude more potent than the parental compound for the series, which carries a native enolpyruvyl group. In this study, we sought to understand how the substituted enolpyruvyl group confers greater potency, by determining cocrystal structures of MbtI with six inhibitors from the series. A switch in binding mode at the MbtI active site is observed for inhibitors carrying a substituted enolpyruvyl group, relative to the parental compound. Computational studies suggest that the change in binding mode, and higher potency, is due to the effect of the substituents on the conformational landscape of the core inhibitor structure. The crystal structures and fluorescence-based thermal shift assays indicate that substituents larger than a methyl group are accommodated in the MbtI active site through significant but localized flexibility in the peptide backbone. These findings have implications for the design of improved inhibitors of MbtI, as well as other chorismate-utilizing enzymes from this family.

PubMed: 22607697
DOI: 10.1021/bi3002067

実験手法

X-RAY DIFFRACTION (2.04 Å)