5ld8
From Proteopedia
GSK3011724A cocrystallised with Mycobacterium tuberculosis H37Rv KasA
Structural highlights
FunctionKASA_MYCTU Part of the mycobacterial fatty acid elongation system FAS-II, which is involved in mycolic acid biosynthesis. Catalyzes the elongation of long chain acyl-ACP substrates by the addition of two carbons from malonyl-ACP to an acyl acceptor (PubMed:11600501, PubMed:12023885, PubMed:12464486, PubMed:16873379, PubMed:22017312, PubMed:24108128). Involved in the initial extension of the mycolate chain and forms monounsaturated fatty acids that averaged 40 carbons in length (PubMed:12464486).[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedPhenotypic screens for bactericidal compounds are starting to yield promising hits against tuberculosis. In this regard, whole-genome sequencing of spontaneous resistant mutants generated against an indazole sulfonamide (GSK3011724A) identifies several specific single-nucleotide polymorphisms in the essential Mycobacterium tuberculosis beta-ketoacyl synthase (kas) A gene. Here, this genomic-based target assignment is confirmed by biochemical assays, chemical proteomics and structural resolution of a KasA-GSK3011724A complex by X-ray crystallography. Finally, M. tuberculosis GSK3011724A-resistant mutants increase the in vitro minimum inhibitory concentration and the in vivo 99% effective dose in mice, establishing in vitro and in vivo target engagement. Surprisingly, the lack of target engagement of the related beta-ketoacyl synthases (FabH and KasB) suggests a different mode of inhibition when compared with other Kas inhibitors of fatty acid biosynthesis in bacteria. These results clearly identify KasA as the biological target of GSK3011724A and validate this enzyme for further drug discovery efforts against tuberculosis. Identification of KasA as the cellular target of an anti-tubercular scaffold.,Abrahams KA, Chung CW, Ghidelli-Disse S, Rullas J, Rebollo-Lopez MJ, Gurcha SS, Cox JA, Mendoza A, Jimenez-Navarro E, Martinez-Martinez MS, Neu M, Shillings A, Homes P, Argyrou A, Casanueva R, Loman NJ, Moynihan PJ, Lelievre J, Selenski C, Axtman M, Kremer L, Bantscheff M, Angulo-Barturen I, Izquierdo MC, Cammack NC, Drewes G, Ballell L, Barros D, Besra GS, Bates RH Nat Commun. 2016 Sep 1;7:12581. doi: 10.1038/ncomms12581. PMID:27581223[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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