5ld8

GSK3011724A cocrystallised with Mycobacterium tuberculosis H37Rv KasA

spinqualitylabelsall models 5ld8, resolution 2.13Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5ld8 is a 2 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.13Å Ligands: 6U5, NA, PG4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function KASA_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). Publication Abstract from PubMed Phenotypic 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Acyl carrier protein synthase 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA