6s43

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

spinqualitylabelsall models 6s43, resolution 1.42Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6s43 is a 4 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.42Å Ligands: FMT, KUE, MG 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 With the growing worldwide prevalence of antibiotic-resistant strains of tuberculosis (TB), new targets are urgently required for the development of treatments with novel modes of action. Fumarate hydratase (fumarase), a vulnerable component of the citric acid cycle in Mycobacterium tuberculosis (Mtb), is a metabolic target that could satisfy this unmet demand. A key challenge in the targeting of Mtb fumarase is its similarity to the human homolog, which shares an identical active site. A potential solution to this selectivity problem was previously found in a high-throughput screening hit that binds in a nonconserved allosteric site. In this work, a structure-activity relationship study was carried out with the determination of further structural biology on the lead series, affording derivatives with sub-micromolar inhibition. Further, the screening of this series against Mtb in vitro identified compounds with potent minimum inhibitory concentrations. Targeting of Fumarate Hydratase from Mycobacterium tuberculosis Using Allosteric Inhibitors with a Dimeric-Binding Mode.,Whitehouse AJ, Libardo MDJ, Kasbekar M, Brear PD, Fischer G, Thomas CJ, Barry CE 3rd, Boshoff HIM, Coyne AG, Abell C J Med Chem. 2019 Dec 12;62(23):10586-10604. doi: 10.1021/acs.jmedchem.9b01203., Epub 2019 Sep 27. PMID:31517489 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Fumarase

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