4FDO

Mycobacterium tuberculosis DprE1 in complex with CT319


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.169 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural basis of inhibition of Mycobacterium tuberculosis DprE1 by benzothiazinone inhibitors.

Batt, S.M.Jabeen, T.Bhowruth, V.Quill, L.Lund, P.A.Eggeling, L.Alderwick, L.J.Futterer, K.Besra, G.S.

(2012) Proc Natl Acad Sci U S A 109: 11354-11359

  • DOI: https://doi.org/10.1073/pnas.1205735109
  • Primary Citation of Related Structures:  
    4FDN, 4FDO, 4FDP, 4FEH, 4FF6

  • PubMed Abstract: 

    Resistance against currently used antitubercular therapeutics increasingly undermines efforts to contain the worldwide tuberculosis (TB) epidemic. Recently, benzothiazinone (BTZ) inhibitors have shown nanomolar potency against both drug-susceptible and multidrug-resistant strains of the tubercle bacillus. However, their proposed mode of action is lacking structural evidence. We report here the crystal structure of the BTZ target, FAD-containing oxidoreductase Mycobacterium tuberculosis DprE1, which is essential for viability. Different crystal forms of ligand-free DprE1 reveal considerable levels of structural flexibility of two surface loops that seem to govern accessibility of the active site. Structures of complexes with the BTZ-derived nitroso derivative CT325 reveal the mode of inhibitor binding, which includes a covalent link to conserved Cys387, and reveal a trifluoromethyl group as a second key determinant of interaction with the enzyme. Surprisingly, we find that a noncovalent complex was formed between DprE1 and CT319, which is structurally identical to CT325 except for an inert nitro group replacing the reactive nitroso group. This demonstrates that binding of BTZ-class inhibitors to DprE1 is not strictly dependent on formation of the covalent link to Cys387. On the basis of the structural and activity data, we propose that the complex of DrpE1 bound to CT325 is a representative of the BTZ-target complex. These results mark a significant step forward in the characterization of a key TB drug target.


  • Organizational Affiliation

    School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
oxidoreductase DprE1481Mycobacterium tuberculosisMutation(s): 0 
Gene Names: dprE1MT3898Rv3790
EC: 1
UniProt
Find proteins for P9WJF1 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WJF1 
Go to UniProtKB:  P9WJF1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WJF1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FAD
Query on FAD

Download Ideal Coordinates CCD File 
B [auth A]FLAVIN-ADENINE DINUCLEOTIDE
C27 H33 N9 O15 P2
VWWQXMAJTJZDQX-UYBVJOGSSA-N
0T5
Query on 0T5

Download Ideal Coordinates CCD File 
C [auth A]3-nitro-N-[(1R)-1-phenylethyl]-5-(trifluoromethyl)benzamide
C16 H13 F3 N2 O3
QAAMVEKRZCRHQM-SNVBAGLBSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.169 
  • Space Group: P 64
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 127.884α = 90
b = 127.884β = 90
c = 64.177γ = 120
Software Package:
Software NamePurpose
CrystalCleardata collection
PHASERphasing
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-07-04
    Type: Initial release
  • Version 1.1: 2012-10-31
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations