5i7a
From Proteopedia
Mycobacterium tuberculosis CysM in complex with the Urea-scaffold inhibitor 1 [3-(3-(3,4-Dichlorophenyl)ureido)benzoic acid]
Structural highlights
FunctionCYSM_MYCTU Catalyzes the formation of a covalent CysO-cysteine adduct via a sulfur transfer, using the thiocarboxylated sulfur carrier protein CysO-COSH as sulfur donor and O-phospho-L-serine (OPS) as sulfur acceptor. Can also use sodium sulfide as sulfur donor in vitro, albeit with less efficiency, but not thiosulfate or thio-nitro-benzoate. O-acetylserine (OAS) is a very poor substrate in comparison with OPS. May be of particular importance for cysteine biosynthesis in the persistent phase of M.tuberculosis.[1] [2] Publication Abstract from PubMedCysteine is an important amino acid in the redox defense of Mycobacterium tuberculosis, primarily as a building block of mycothiol. Genetic studies have implicated de novo cysteine biosynthesis in pathogen survival in infected macrophages, in particular for persistent M. tuberculosis. Here, we report on the identification and characterization of potent inhibitors of CysM, a critical enzyme in cysteine biosynthesis during dormancy. A screening campaign of 17312 compounds identified ligands that bind to the active site with micromolar affinity. These were characterized in terms of their inhibitory potencies and structure-activity relationships through hit expansion guided by three-dimensional structures of enzyme-inhibitor complexes. The top compound binds to CysM with 300 nM affinity and displays selectivity over the mycobacterial homologues CysK1 and CysK2. Notably, two inhibitors show significant potency in a nutrient-starvation model of dormancy of Mycobacterium tuberculosis, with little or no cytotoxicity toward mammalian cells. Inhibitors of the Cysteine Synthase CysM with Antibacterial Potency against Dormant Mycobacterium tuberculosis.,Brunner K, Maric S, Reshma RS, Almqvist H, Seashore-Ludlow B, Gustavsson AL, Poyraz O, Yogeeswari P, Lundback T, Vallin M, Sriram D, Schnell R, Schneider G J Med Chem. 2016 Jul 28;59(14):6848-59. doi: 10.1021/acs.jmedchem.6b00674. Epub, 2016 Jul 13. PMID:27379713[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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