5f91

Fumarate hydratase of Mycobacterium tuberculosis in complex with formate and allosteric modulator (N-(5-(azepan-1-ylsulfonyl)-2-methoxyphenyl)-2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetamide)Fumarate hydratase of Mycobacterium tuberculosis in complex with formate and allosteric modulator (N-(5-(azepan-1-ylsulfonyl)-2-methoxyphenyl)-2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetamide)

Structural highlights 5f91 is a 4 chain structure with sequence from Mycobacterium tuberculosis CDC1551. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.998Å Ligands: , , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function FUMC_MYCTU Catalyzes the reversible addition of water to fumarate to give L-malate. Publication Abstract from PubMed Enzymes in essential metabolic pathways are attractive targets for the treatment of bacterial diseases, but in many cases, the presence of homologous human enzymes makes them impractical candidates for drug development. Fumarate hydratase, an essential enzyme in the tricarboxylic acid (TCA) cycle, has been identified as one such potential therapeutic target in tuberculosis. We report the discovery of the first small molecule inhibitor, to our knowledge, of the Mycobacterium tuberculosis fumarate hydratase. A crystal structure at 2.0-A resolution of the compound in complex with the protein establishes the existence of a previously unidentified allosteric regulatory site. This allosteric site allows for selective inhibition with respect to the homologous human enzyme. We observe a unique binding mode in which two inhibitor molecules interact within the allosteric site, driving significant conformational changes that preclude simultaneous substrate and inhibitor binding. Our results demonstrate the selective inhibition of a highly conserved metabolic enzyme that contains identical active site residues in both the host and the pathogen. Selective small molecule inhibitor of the Mycobacterium tuberculosis fumarate hydratase reveals an allosteric regulatory site.,Kasbekar M, Fischer G, Mott BT, Yasgar A, Hyvonen M, Boshoff HI, Abell C, Barry CE 3rd, Thomas CJ Proc Natl Acad Sci U S A. 2016 Jul 5;113(27):7503-8. doi:, 10.1073/pnas.1600630113. Epub 2016 Jun 20. PMID:27325754 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Fumarase

spinqualitylabelsall models 5f91, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image