3NOF

Mycobacterium tuberculosis thioredoxin C C40S mutant


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.182 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Structure of Mycobacterium tuberculosis thioredoxin in complex with quinol inhibitor PMX464

Hall, G.Bradshaw, T.D.Laughton, C.A.Stevens, M.F.Emsley, J.

(2011) Protein Sci 20: 210-215

  • DOI: https://doi.org/10.1002/pro.533
  • Primary Citation of Related Structures:  
    3NOF, 3O6T

  • PubMed Abstract: 

    Thioredoxin (Trx) plays a critical role in the regulation of cellular redox homeostasis. Many disease causing pathogens rely on the Trx redox system for survival in conditions of environmental stress. The Trx redox system has been implicated in the resistance of Mycobacterium tuberculosis (Mtb) to phagocytosis. Trx is able to reduce a variety of target substrates and reactive oxygen species (ROS) through the cyclization of its active site dithiol to the oxidized disulphide Cys37-Cys40. Here we report the crystal structure of the Mtb Trx C active site mutant C40S (MtbTrxCC40S) in isolation and in complex with the hydroxycyclohexadienone inhibitor PMX464. We observe PMX464 is covalently bound to the active site residue Cys37 through Michael addition of the cyclohexadienone ring and also forms noncovalent contacts which mimic the binding of natural Trx ligands. In comparison with the ligand free MtbTrxCC40S structure a conformational change occurs in the PMX464 complex involving movement of helix α2 and the active site loop. These changes are almost identical to those observed for helix α2 in human Trx ligand complexes. Whereas the ligand free structure forms a homodimer the inhibitor complex unexpectedly forms a different dimer with one PMX464 molecule bound at the interface. This 2:1 MtbTrxCC40S-PMX464 complex is also observed using mass spectrometry measurements. This structure provides an unexpected scaffold for the design of improved Trx inhibitors targeted at developing treatments for tuberculosis.


  • Organizational Affiliation

    Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Thioredoxin TrxC
A, B
118Mycobacterium tuberculosis H37RaMutation(s): 1 
Gene Names: TrxC
UniProt
Find proteins for A5U9P2 (Mycobacterium tuberculosis (strain ATCC 25177 / H37Ra))
Explore A5U9P2 
Go to UniProtKB:  A5U9P2
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA5U9P2
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.182 
  • Space Group: P 65
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 75.269α = 90
b = 75.269β = 90
c = 96.028γ = 120
Software Package:
Software NamePurpose
DNAdata collection
PHASESphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-11-10
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description