3ST6

Structure of a M. tuberculosis Synthase, MbtI, in Complex with an Isochorismate Analogue Inhibitor

Summary for 3ST6

• Entry DOI: 10.2210/pdb3st6/pdb
• Related: 3RV6 3RV7 3RV8 3RV9
• Descriptor: Isochorismate synthase/isochorismate-pyruvate lyase mbtI, 3-[(1-carboxyethenyl)oxy]-2-hydroxybenzoic acid (3 entities in total)
• Functional Keywords: structural genomics, tb structural genomics consortium, tbsgc, mixed alpha/beta fold, salicylate synthase, chorismate binding, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 4
• Total formula weight: 195693.29

Authors

Chi, G.,Bulloch, E.M.M.,Manos-Turvey, A.,Payne, R.J.,Lott, J.S.,TB Structural Genomics Consortium (TBSGC) (deposition date: 2011-07-08, release date: 2012-05-30, Last modification date: 2023-11-01)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.75 Å)