6THC

Crystal structure of Mycobacterium smegmatis CoaB in complex with CTP and (4-hydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone

6THC の概要

• エントリーDOI: 10.2210/pdb6thc/pdb
• 分子名称: Coenzyme A biosynthesis bifunctional protein CoaBC, CYTIDINE-5'-TRIPHOSPHATE, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: coabc, bifunctional phosphopantothenoylcysteine decarboxylase/phosphopantothenate-cysteine ligase, phosphopantothenate-cysteine ligase, phosphopantothenoylcysteine decarboxylase, phosphopantothenoylcysteine synthetase, ligase
• 由来する生物種: Mycolicibacterium smegmatis
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 102843.32

構造登録者

Mendes, V.,Blaszczyk, M.,Bryant, O.,Cory-Wright, J.,Blundell, T.L. (登録日: 2019-11-19, 公開日: 2020-11-25, 最終更新日: 2024-01-24)

主引用文献

Mendes, V.,Green, S.R.,Evans, J.C.,Hess, J.,Blaszczyk, M.,Spry, C.,Bryant, O.,Cory-Wright, J.,Chan, D.S.,Torres, P.H.M.,Wang, Z.,Nahiyaan, N.,O'Neill, S.,Damerow, S.,Post, J.,Bayliss, T.,Lynch, S.L.,Coyne, A.G.,Ray, P.C.,Abell, C.,Rhee, K.Y.,Boshoff, H.I.M.,Barry, C.E.,Mizrahi, V.,Wyatt, P.G.,Blundell, T.L.
Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site.
Nat Commun, 12:143-143, 2021

PubMed Abstract: Coenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous metabolic pathways and cellular processes, and its biosynthetic pathway has raised substantial interest as a drug target against multiple pathogens including Mycobacterium tuberculosis. The biosynthesis of CoA is performed in five steps, with the second and third steps being catalysed in the vast majority of prokaryotes, including M. tuberculosis, by a single bifunctional protein, CoaBC. Depletion of CoaBC was found to be bactericidal in M. tuberculosis. Here we report the first structure of a full-length CoaBC, from the model organism Mycobacterium smegmatis, describe how it is organised as a dodecamer and regulated by CoA thioesters. A high-throughput biochemical screen focusing on CoaB identified two inhibitors with different chemical scaffolds. Hit expansion led to the discovery of potent and selective inhibitors of M. tuberculosis CoaB, which we show to bind to a cryptic allosteric site within CoaB.

PubMed: 33420031
DOI: 10.1038/s41467-020-20224-x

実験手法

X-RAY DIFFRACTION (2.033 Å)