4FDP

Mycobacterium tuberculosis DprE1 - monoclinic crystal form


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.23 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.193 

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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 DprE1
A, B
481Mycobacterium 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
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.23 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.193 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.97α = 90
b = 83.62β = 103.91
c = 81.37γ = 90
Software Package:
Software NamePurpose
GDAdata collection
SHELXDphasing
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling

Structure Validation

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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