5TCJ

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

Summary for 5TCJ

• Entry DOI: 10.2210/pdb5tcj/pdb
• Related: 5TCF 5TCG 5TCH 5TCI
• Descriptor: Tryptophan synthase alpha chain, Tryptophan synthase beta chain, MALONATE ION, ... (8 entities in total)
• Functional Keywords: plp, heterotetramer, amino acid biosynthesis, substrate channeling, allostery, structural genomics, center for structural genomics of infectious diseases, csgid, lyase
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv); More
• Total number of polymer chains: 8
• Total formula weight: 292675.20

Authors

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) (deposition date: 2016-09-15, release date: 2017-05-31, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.4 Å)