3SAD

Crystal structure of Mycobacterium tuberculosis malate synthase in complex with 4-(2-mehtylphenyl)-2,4-dioxobutanoic acid inhibitor

Summary for 3SAD

• Entry DOI: 10.2210/pdb3sad/pdb
• Related: 1N8I 1N8W 2GQ3 3S9I 3S9Z 3SAZ 3SB0
• Descriptor: Malate synthase G, MAGNESIUM ION, 4-(2-methylphenyl)-2,4-dioxobutanoic acid, ... (4 entities in total)
• Functional Keywords: inhibitor complex, structural genomics, mycobacterium tuberculosis structural proteomics project, xmtb, malate synthase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 1
• Total formula weight: 80735.84

Authors

Krieger, I.V.,Sun, Q.,Sacchettini, J.C.,Mycobacterium Tuberculosis Structural Proteomics Project (XMTB) (deposition date: 2011-06-02, release date: 2012-11-07, Last modification date: 2023-09-13)

Primary citation

Krieger, I.V.,Freundlich, J.S.,Gawandi, V.B.,Roberts, J.P.,Gawandi, V.B.,Sun, Q.,Owen, J.L.,Fraile, M.T.,Huss, S.I.,Lavandera, J.L.,Ioerger, T.R.,Sacchettini, J.C.
Structure-guided discovery of phenyl-diketo acids as potent inhibitors of M. tuberculosis malate synthase.
Chem.Biol., 19:1556-1567, 2012

PubMed Abstract: The glyoxylate shunt plays an important role in fatty acid metabolism and has been shown to be critical to survival of several pathogens involved in chronic infections. For Mycobacterium tuberculosis (Mtb), a strain with a defective glyoxylate shunt was previously shown to be unable to establish infection in a mouse model. We report the development of phenyl-diketo acid (PDKA) inhibitors of malate synthase (GlcB), one of two glyoxylate shunt enzymes, using structure-based methods. PDKA inhibitors were active against Mtb grown on acetate, and overexpression of GlcB ameliorated this inhibition. Crystal structures of complexes of GlcB with PDKA inhibitors guided optimization of potency. A selected PDKA compound demonstrated efficacy in a mouse model of tuberculosis. The discovery of these PDKA derivatives provides chemical validation of GlcB as an attractive target for tuberculosis therapeutics.

PubMed: 23261599
DOI: 10.1016/j.chembiol.2012.09.018

Experimental method

X-RAY DIFFRACTION (1.82 Å)