5TCI

Crystal structure of tryptophan synthase from M. tuberculosis - BRD4592-bound form

5TCI の概要

• エントリーDOI: 10.2210/pdb5tci/pdb
• 関連するPDBエントリー: 5TCF 5TCG 5TCH 5TCJ
• 分子名称: Tryptophan synthase alpha chain, Tryptophan synthase beta chain, MALONATE ION, ... (6 entities in total)
• 機能のキーワード: plp, heterotetramer, amino acid biosynthesis, substrate channeling, allostery, structural genomics, center for structural genomics of infectious diseases, csgid, lyase
• 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: 8
• 化学式量合計: 290704.40

構造登録者

Michalska, K.,Maltseva, N.,Jedrzejczak, R.,Wellington, S.,Nag, P.P.,Fisher, S.L.,Schreiber, S.L.,Hung, D.T.,Joachimiak, A.,Center for Structural Genomics of Infectious Diseases (CSGID) (登録日: 2016-09-15, 公開日: 2017-05-31, 最終更新日: 2023-11-15)

主引用文献

Wellington, S.,Nag, P.P.,Michalska, K.,Johnston, S.E.,Jedrzejczak, R.P.,Kaushik, V.K.,Clatworthy, A.E.,Siddiqi, N.,McCarren, P.,Bajrami, B.,Maltseva, N.I.,Combs, S.,Fisher, S.L.,Joachimiak, A.,Schreiber, S.L.,Hung, D.T.
A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase.
Nat. Chem. Biol., 13:943-950, 2017

PubMed Abstract: New antibiotics with novel targets are greatly needed. Bacteria have numerous essential functions, but only a small fraction of such processes-primarily those involved in macromolecular synthesis-are inhibited by current drugs. Targeting metabolic enzymes has been the focus of recent interest, but effective inhibitors have been difficult to identify. We describe a synthetic azetidine derivative, BRD4592, that kills Mycobacterium tuberculosis (Mtb) through allosteric inhibition of tryptophan synthase (TrpAB), a previously untargeted, highly allosterically regulated enzyme. BRD4592 binds at the TrpAB α-β-subunit interface and affects multiple steps in the enzyme's overall reaction, resulting in inhibition not easily overcome by changes in metabolic environment. We show that TrpAB is required for the survival of Mtb and Mycobacterium marinum in vivo and that this requirement may be independent of an adaptive immune response. This work highlights the effectiveness of allosteric inhibition for targeting proteins that are naturally highly dynamic and that are essential in vivo, despite their apparent dispensability under in vitro conditions, and suggests a framework for the discovery of a next generation of allosteric inhibitors.

PubMed: 28671682
DOI: 10.1038/nchembio.2420

実験手法

X-RAY DIFFRACTION (2.45 Å)