4P8T

Crystal structure of M. tuberculosis DprE1 in complex with the non-covalent inhibitor QN129


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.55 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.187 

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
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 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
R26
Query on R26

Download Ideal Coordinates CCD File 
D [auth A],
H [auth B]
3-[(4-cyanobenzyl)amino]-6-(trifluoromethyl)quinoxaline-2-carboxylic acid
C18 H11 F3 N4 O2
RFEBDZANCVHDLP-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
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.55 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.187 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.231α = 90
b = 83.039β = 102.84
c = 80.729γ = 90
Software Package:
Software NamePurpose
XDSdata scaling
PHASERphasing
REFMACrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
European CommissionSwitzerland260872

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: 2023-12-27
    Changes: Data collection, Database references, Refinement description