PDBsum entry 5tcf

Lyase

PDB id: 5tcf

Contents

Protein chains

249 a.a.

405 a.a.

Ligands

MLI ×4

FMT ×21

Metals

__K ×3

Waters ×469

PDB id:

5tcf

Name:

Lyase

Title:

Crystal structure of tryptophan synthase from m. Tuberculosis - ligand-free form

Structure:

Tryptophan synthase alpha chain. Chain: a, g, e, c. Engineered: yes. Tryptophan synthase beta chain. Chain: b, h, f, d. Fragment: unp 13-422. Engineered: yes. Other_details: lys101 is attached to plp

Source:

Mycobacterium tuberculosis (strain atcc 25618 / h37rv). Organism_taxid: 83332. Strain: atcc 25618 / h37rv. Gene: trpa, rv1613, mtcy01b2.05. Expressed in: escherichia coli. Expression_system_taxid: 469008. Gene: trpb, rv1612, mtcy01b2.04.

Resolution:

2.46Å R-factor: 0.176 R-free: 0.207

Authors:

K.Michalska,N.Maltseva,R.Jedrzejczak,A.Joachimiak,Center For Structural Genomics Of Infectious Diseases (Csgid)

Key ref:

S.Wellington et al. (2017). A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase. Nat Chem Biol, 13, 943-950. PubMed id: 28671682

Date:

15-Sep-16 Release date: 31-May-17

Protein chains

P9WFY1  (TRPA_MYCTU) -  Tryptophan synthase alpha chain from Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)

Seq: 270 a.a.

Struc: 249 a.a.

Protein chains

P9WFX9  (TRPB_MYCTU) -  Tryptophan synthase beta chain from Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)

Seq: 421 a.a.

Struc: 405 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chains A, B, G, H, E, F, C, D: E.C.4.2.1.20 - tryptophan synthase.
• Pathway: Tryptophan Biosynthesis
• Reaction: (1S,2R)-1-C-(indol-3-yl)glycerol 3-phosphate + L-serine = D-glyceraldehyde 3-phosphate + L-tryptophan + H2O

(1S,2R)-1-C-(indol-3-yl)glycerol 3-phosphate + L-serine (Bound ligand (Het Group name = MLI) matches with 75.00% similarity) = D-glyceraldehyde 3-phosphate + L-tryptophan + H2O

• Cofactor: Pyridoxal 5'-phosphate

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

Nat Chem Biol 13:943-950 (2017)

PubMed id: 28671682

A small-molecule allosteric inhibitor of Mycobacterium tuberculosis tryptophan synthase.

S.Wellington, P.P.Nag, K.Michalska, S.E.Johnston, R.P.Jedrzejczak, V.K.Kaushik, A.E.Clatworthy, N.Siddiqi, P.McCarren, B.Bajrami, N.I.Maltseva, S.Combs, S.L.Fisher, A.Joachimiak, S.L.Schreiber, D.T.Hung.

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.