3sb0 | pdb_00003sb0

Crystal structure of Mycobacterium tuberculosis malate synthase in complex with 4-(2-chloro-6-fluoro-3-methylphenyl)-2,4-dioxobutanoic acid inhibitor

spinqualitylabelsall models 3sb0, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3sb0 is a 1 chain structure with sequence from "bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: I93, MG Related: 1n8i, 1n8w, 3saz, 3s9i, 3s9z, 3sad Gene: glcB, GlcB (Rv1837c), MT1885, MTCY1A11.06, Rv1837c ("Bacillus tuberculosis" (Zopf 1883) Klein 1884) Activity: Malate synthase, with EC number 2.3.3.9 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [MASZ_MYCTU] Involved in the glycolate utilization. Catalyzes the condensation and subsequent hydrolysis of acetyl-coenzyme A (acetyl-CoA) and glyoxylate to form malate and CoA (By similarity).[HAMAP-Rule:MF_00641] Publication Abstract from PubMed 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. Structure-guided discovery of phenyl-diketo acids as potent inhibitors of M. tuberculosis malate synthase.,Krieger IV, Freundlich JS, Gawandi VB, Roberts JP, Gawandi VB, Sun Q, Owen JL, Fraile MT, Huss SI, Lavandera JL, Ioerger TR, Sacchettini JC Chem Biol. 2012 Dec 21;19(12):1556-67. doi: 10.1016/j.chembiol.2012.09.018. PMID:23261599 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Malate synthase

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