4P8C

Crystal structure of M. tuberculosis DprE1 in complex with the non-covalent inhibitor QN127


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.239 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.204 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

2-Carboxyquinoxalines Kill Mycobacterium tuberculosis through Noncovalent Inhibition of DprE1.

Neres, J.Hartkoorn, R.C.Chiarelli, L.R.Gadupudi, R.Pasca, M.R.Mori, G.Venturelli, A.Savina, S.Makarov, V.Kolly, G.S.Molteni, E.Binda, C.Dhar, N.Ferrari, S.Brodin, P.Delorme, V.Landry, V.de Jesus Lopes Ribeiro, A.L.Farina, D.Saxena, P.Pojer, F.Carta, A.Luciani, R.Porta, A.Zanoni, G.De Rossi, E.Costi, M.P.Riccardi, G.Cole, S.T.

(2015) ACS Chem Biol 10: 705-714

  • DOI: https://doi.org/10.1021/cb5007163
  • Primary Citation of Related Structures:  
    4CVY, 4P8C, 4P8K, 4P8L, 4P8M, 4P8N, 4P8P, 4P8T, 4P8Y

  • PubMed Abstract: 

    Phenotypic screening of a quinoxaline library against replicating Mycobacterium tuberculosis led to the identification of lead compound Ty38c (3-((4-methoxybenzyl)amino)-6-(trifluoromethyl)quinoxaline-2-carboxylic acid). With an MIC99 and MBC of 3.1 μM, Ty38c is bactericidal and active against intracellular bacteria. To investigate its mechanism of action, we isolated mutants resistant to Ty38c and sequenced their genomes. Mutations were found in rv3405c, coding for the transcriptional repressor of the divergently expressed rv3406 gene. Biochemical studies clearly showed that Rv3406 decarboxylates Ty38c into its inactive keto metabolite. The actual target was then identified by isolating Ty38c-resistant mutants of an M. tuberculosis strain lacking rv3406. Here, mutations were found in dprE1, encoding the decaprenylphosphoryl-d-ribose oxidase DprE1, essential for biogenesis of the mycobacterial cell wall. Genetics, biochemical validation, and X-ray crystallography revealed Ty38c to be a noncovalent, noncompetitive DprE1 inhibitor. Structure-activity relationship studies generated a family of DprE1 inhibitors with a range of IC50's and bactericidal activity. Co-crystal structures of DprE1 in complex with eight different quinoxaline analogs provided a high-resolution interaction map of the active site of this extremely vulnerable target in M. tuberculosis.


  • Organizational Affiliation

    †More Medicines for Tuberculosis (MM4TB) Consortium (www.mm4tb.org).


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Probable decaprenylphosphoryl-beta-D-ribose oxidase
A, B
480Mycobacterium tuberculosis H37RvMutation(s): 0 
Gene Names: dprE1Rv3790MT3898
EC: 1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FAD
Query on FAD

Download Ideal Coordinates CCD File 
C [auth A],
G [auth B]
FLAVIN-ADENINE DINUCLEOTIDE
C27 H33 N9 O15 P2
VWWQXMAJTJZDQX-UYBVJOGSSA-N
Y22
Query on Y22

Download Ideal Coordinates CCD File 
D [auth A],
H [auth B]
6-(trifluoromethyl)-3-{[4-(trifluoromethyl)benzyl]amino}quinoxaline-2-carboxylic acid
C18 H11 F6 N3 O2
FEJSMMIZTOMLEL-UHFFFAOYSA-N
2J3
Query on 2J3

Download Ideal Coordinates CCD File 
F [auth A](2R)-2-{[(2R)-2-{[(2R)-2-hydroxypropyl]oxy}propyl]oxy}propan-1-ol
C9 H20 O4
LCZVSXRMYJUNFX-IWSPIJDZSA-N
IMD
Query on IMD

Download Ideal Coordinates CCD File 
E [auth A]IMIDAZOLE
C3 H5 N2
RAXXELZNTBOGNW-UHFFFAOYSA-O
Binding Affinity Annotations 
IDSourceBinding Affinity
Y22 Binding MOAD:  4P8C IC50: 120 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.239 
  • R-Value Work: 0.202 
  • R-Value Observed: 0.204 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.678α = 90
b = 84.158β = 103.17
c = 80.905γ = 90
Software Package:
Software NamePurpose
XDSdata scaling
PHASERphasing
REFMACrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-12-10
    Type: Initial release
  • Version 1.1: 2015-02-04
    Changes: Derived calculations
  • Version 1.2: 2015-04-01
    Changes: Database references
  • Version 1.3: 2017-11-22
    Changes: Derived calculations, Other, Refinement description, Source and taxonomy
  • Version 1.4: 2023-09-27
    Changes: Data collection, Database references, Refinement description