5DTW

Crystal structure of M. tuberculosis EchA6 bound to C20-CoA

5DTW の概要

• エントリーDOI: 10.2210/pdb5dtw/pdb
• 関連するPDBエントリー: 5DTP
• 分子名称: enoyl-CoA hydratase echA6, Arachinoyl-CoA (3 entities in total)
• 機能のキーワード: enoyl-coa hydratase-like, lyase, lipid binding protein
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 171505.21

構造登録者

Cox, J.A.G.,Besra, G.S.,Futterer, K. (登録日: 2015-09-18, 公開日: 2016-01-20, 最終更新日: 2024-01-10)

主引用文献

Cox, J.A.,Abrahams, K.A.,Alemparte, C.,Ghidelli-Disse, S.,Rullas, J.,Angulo-Barturen, I.,Singh, A.,Gurcha, S.S.,Nataraj, V.,Bethell, S.,Remuinan, M.J.,Encinas, L.,Jervis, P.J.,Cammack, N.C.,Bhatt, A.,Kruse, U.,Bantscheff, M.,Futterer, K.,Barros, D.,Ballell, L.,Drewes, G.,Besra, G.S.
THPP target assignment reveals EchA6 as an essential fatty acid shuttle in mycobacteria.
Nat Microbiol, 1:15006-15006, 2016

PubMed Abstract: 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.

PubMed: 27571973
DOI: 10.1038/nmicrobiol.2015.6

実験手法

X-RAY DIFFRACTION (2.439 Å)