5OCW

Structure of Mycobacterium tuberculosis tryptophan synthase in space group F222

5OCW の概要

• エントリーDOI: 10.2210/pdb5ocw/pdb
• 分子名称: Tryptophan synthase alpha chain, Tryptophan synthase beta chain, 2-[({3-HYDROXY-2-METHYL-5-[(PHOSPHONOOXY)METHYL]PYRIDIN-4-YL}METHYL)AMINO]ACRYLIC ACID (3 entities in total)
• 機能のキーワード: tryptophan synthesis mycobacterium tuberculosis, electron transport
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv); 詳細
• タンパク質・核酸の鎖数: 24
• 化学式量合計: 925268.20

構造登録者

Futterer, K.,Abrahams, K.,Cox, J.A.G.,Besra, G.S. (登録日: 2017-07-03, 公開日: 2017-07-12, 最終更新日: 2024-01-17)

主引用文献

Abrahams, K.A.,Cox, J.A.G.,Futterer, K.,Rullas, J.,Ortega-Muro, F.,Loman, N.J.,Moynihan, P.J.,Perez-Herran, E.,Jimenez, E.,Esquivias, J.,Barros, D.,Ballell, L.,Alemparte, C.,Besra, G.S.
Inhibiting mycobacterial tryptophan synthase by targeting the inter-subunit interface.
Sci Rep, 7:9430-9430, 2017

PubMed Abstract: Drug discovery efforts against the pathogen Mycobacterium tuberculosis (Mtb) have been advanced through phenotypic screens of extensive compound libraries. Such a screen revealed sulfolane 1 and indoline-5-sulfonamides 2 and 3 as potent inhibitors of mycobacterial growth. Optimization in the sulfolane series led to compound 4, which has proven activity in an in vivo murine model of Mtb infection. Here we identify the target and mode of inhibition of these compounds based on whole genome sequencing of spontaneous resistant mutants, which identified mutations locating to the essential α- and β-subunits of tryptophan synthase. Over-expression studies confirmed tryptophan synthase as the biological target. Biochemical techniques probed the mechanism of inhibition, revealing the mutant enzyme complex incurs a fitness cost but does not prevent inhibitor binding. Mapping of the resistance conferring mutations onto a low-resolution crystal structure of Mtb tryptophan synthase showed they locate to the interface between the α- and β-subunits. The discovery of anti-tubercular agents inhibiting tryptophan synthase highlights the therapeutic potential of this enzyme and draws attention to the prospect of other amino acid biosynthetic pathways as future Mtb drug targets.

PubMed: 28842600
DOI: 10.1038/s41598-017-09642-y

実験手法

X-RAY DIFFRACTION (4 Å)