5du8

Crystal structure of M. tuberculosis EchA6 bound to GSK572A

spinqualitylabelsall models 5du8, resolution 2.23Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5du8 is a 3 chain structure with sequence from "bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 5FK Gene: echA6, Rv0905, MTCY31.33 ("Bacillus tuberculosis" (Zopf 1883) Klein 1884) Activity: Enoyl-CoA hydratase, with EC number 4.2.1.17 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [ECHA6_MYCTU] Could possibly oxidize fatty acids using specific components. Publication Abstract from PubMed Phenotypic screens for bactericidal compounds against drug-resistant tuberculosis are beginning to yield novel inhibitors. However, reliable target identification remains challenging. Here, we show that tetrahydropyrazo[1,5-a]pyrimidine-3-carboxamide (THPP) selectively pulls down EchA6 in a stereospecific manner, instead of the previously assigned target Mycobacterium tuberculosis MmpL3. While homologous to mammalian enoyl-coenzyme A (CoA) hydratases, EchA6 is non-catalytic yet essential and binds long-chain acyl-CoAs. THPP inhibitors compete with CoA-binding, suppress mycolic acid synthesis, and are bactericidal in a mouse model of chronic tuberculosis infection. A point mutation, W133A, abrogated THPP-binding and increased both the in vitro minimum inhibitory concentration and the in vivo effective dose 99 in mice. Surprisingly, EchA6 interacts with selected enzymes of fatty acid synthase II (FAS-II) in bacterial two-hybrid assays, suggesting essentiality may be linked to feeding long-chain fatty acids to FAS-II. Finally, our data show that spontaneous resistance-conferring mutations can potentially obscure the actual target or alternative targets of small molecule inhibitors. THPP target assignment reveals EchA6 as an essential fatty acid shuttle in mycobacteria.,Cox JA, Abrahams KA, Alemparte C, Ghidelli-Disse S, Rullas J, Angulo-Barturen I, Singh A, Gurcha SS, Nataraj V, Bethell S, Remuinan MJ, Encinas L, Jervis PJ, Cammack NC, Bhatt A, Kruse U, Bantscheff M, Futterer K, Barros D, Ballell L, Drewes G, Besra GS Nat Microbiol. 2016 Jan 18;1:15006. doi: 10.1038/nmicrobiol.2015.6. PMID:27571973 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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