5cjm

Crystal structure of Mycobacterium tuberculosis malate synthase in complex with 4H-thieno[3,2-b]pyrrole-5-carboxylic acid

spinqualitylabelsall models 5cjm, resolution 2.13Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5cjm is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 4WL, MG NonStd Res: CSO 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 Fragment screening and high-throughput screening are complementary approaches that go hand in hand with structural biology to explore the binding capabilities of an active site and to provide diversity for inhibitor design. We used fragment-based approaches on malate synthase (GlcB) from Mycobacterium tuberculosis and discovered several novel binding chemotypes. In addition, the crystal structures of GlcB in complex with these fragments indicated conformational changes in the active site hypothesized to represent states the enzyme assumes in the substrate-product exchange during catalysis. Additional structures of the late product formation stage (in complex with malate) and of the apo form of GlcB supported that hypothesis. Comparative analysis of GlcB structures in complex with 18 fragments allowed us to characterize the preferred chemotypes and their modes of binding. The fragment structures showed a hydrogen bond to the backbone carbonyl of Met631, we successfully incorporated fragment moiety into an existing phenyl-diketo acid (PDKA) inhibitor to take advantage of this interaction. The result was 100-fold more potent than the parent PDKA indole-containing inhibitor with an IC 50 value of 20 nM. Mycobacterium tuberculosis Malate Synthase Structures with Fragments Reveal a Portal for Substrate/Product Exchange.,Huang HL, Krieger IV, Parai MK, Gawandi VB, Sacchettini JC J Biol Chem. 2016 Oct 13. pii: jbc.M116.750877. PMID:27738104 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Malate synthase 3D structures

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