5TCF

Crystal structure of tryptophan synthase from M. tuberculosis - ligand-free form


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.46 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.176 

wwPDB Validation   3D Report Full Report


This is version 1.5 of the entry. See complete history


Literature

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

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.

(2017) Nat Chem Biol 13: 943-950

  • DOI: https://doi.org/10.1038/nchembio.2420
  • Primary Citation of Related Structures:  
    5TCF, 5TCG, 5TCH, 5TCI, 5TCJ

  • 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.


  • Organizational Affiliation

    The Broad Institute, Cambridge, Massachusetts, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tryptophan synthase alpha chainA,
C [auth G],
E,
G [auth C]
276Mycobacterium tuberculosis H37RvMutation(s): 0 
Gene Names: trpARv1613MTCY01B2.05
EC: 4.2.1.20
UniProt
Find proteins for P9WFY1 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WFY1 
Go to UniProtKB:  P9WFY1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WFY1
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Tryptophan synthase beta chainB,
D [auth H],
F,
H [auth D]
410Mycobacterium tuberculosis H37RvMutation(s): 0 
Gene Names: trpBRv1612MTCY01B2.04
EC: 4.2.1.20
UniProt
Find proteins for P9WFX9 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WFX9 
Go to UniProtKB:  P9WFX9
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WFX9
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
MLI
Query on MLI

Download Ideal Coordinates CCD File 
BA [auth C],
I [auth A],
Q [auth G],
W [auth E]
MALONATE ION
C3 H2 O4
OFOBLEOULBTSOW-UHFFFAOYSA-L
FMT
Query on FMT

Download Ideal Coordinates CCD File 
AA [auth F]
CA [auth C]
DA [auth D]
EA [auth D]
FA [auth D]
AA [auth F],
CA [auth C],
DA [auth D],
EA [auth D],
FA [auth D],
GA [auth D],
HA [auth D],
IA [auth D],
J [auth A],
JA [auth D],
K [auth B],
L [auth B],
M [auth B],
N [auth B],
R [auth G],
S [auth G],
T [auth H],
U [auth H],
X [auth E],
Y [auth F],
Z [auth F]
FORMIC ACID
C H2 O2
BDAGIHXWWSANSR-UHFFFAOYSA-N
K
Query on K

Download Ideal Coordinates CCD File 
O [auth B],
P [auth B],
V [auth H]
POTASSIUM ION
K
NPYPAHLBTDXSSS-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
LLP
Query on LLP
B,
D [auth H],
F,
H [auth D]
L-PEPTIDE LINKINGC14 H22 N3 O7 PLYS
Experimental Data & Validation

Experimental Data

Unit Cell:
Length ( Å )Angle ( ˚ )
a = 135.137α = 90
b = 157.989β = 90
c = 166.651γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesHHSN272201200026C
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesHHSN272200700058C
Structure-guided Drug Discovery CoalitionCanada--

Revision History  (Full details and data files)

  • Version 1.0: 2017-05-31
    Type: Initial release
  • Version 1.1: 2017-09-13
    Changes: Author supporting evidence
  • Version 1.2: 2017-10-25
    Changes: Database references
  • Version 1.3: 2022-04-13
    Changes: Author supporting evidence, Database references, Derived calculations
  • Version 1.4: 2023-10-04
    Changes: Data collection, Refinement description
  • Version 1.5: 2023-11-15
    Changes: Data collection