4P8Y

Crystal structure of M. tuberculosis DprE1 in complex with the non-covalent inhibitor Ty21c


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.01 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.209 
  • R-Value Observed: 0.211 

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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
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.01 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.209 
  • R-Value Observed: 0.211 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.064α = 90
b = 83.312β = 103
c = 80.659γ = 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