4DRE

Mycobacterium tuberculosis InhA in complex with NADH


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.249 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.195 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Towards a new tuberculosis drug: pyridomycin - nature's isoniazid.

Hartkoorn, R.C.Sala, C.Neres, J.Pojer, F.Magnet, S.Mukherjee, R.Uplekar, S.Boy-Rottger, S.Altmann, K.H.Cole, S.T.

(2012) EMBO Mol Med 4: 1032-1042

  • DOI: https://doi.org/10.1002/emmm.201201689
  • Primary Citation of Related Structures:  
    4DQU, 4DRE, 4DTI

  • PubMed Abstract: 

    Tuberculosis, a global threat to public health, is becoming untreatable due to widespread drug resistance to frontline drugs such as the InhA-inhibitor isoniazid. Historically, by inhibiting highly vulnerable targets, natural products have been an important source of antibiotics including potent anti-tuberculosis agents. Here, we describe pyridomycin, a compound produced by Dactylosporangium fulvum with specific cidal activity against mycobacteria. By selecting pyridomycin-resistant mutants of Mycobacterium tuberculosis, whole-genome sequencing and genetic validation, we identified the NADH-dependent enoyl- (Acyl-Carrier-Protein) reductase InhA as the principal target and demonstrate that pyridomycin inhibits mycolic acid synthesis in M. tuberculosis. Furthermore, biochemical and structural studies show that pyridomycin inhibits InhA directly as a competitive inhibitor of the NADH-binding site, thereby identifying a new, druggable pocket in InhA. Importantly, the most frequently encountered isoniazid-resistant clinical isolates remain fully susceptible to pyridomycin, thus opening new avenues for drug development. →See accompanying article http://dx.doi.org/10.1002/emmm.201201811.


  • Organizational Affiliation

    Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Enoyl-[acyl-carrier-protein] reductase [NADH]269Mycobacterium tuberculosisMutation(s): 0 
Gene Names: inhAMT1531MTCY277.05Rv1484
EC: 1.3.1.9
UniProt
Find proteins for P9WGR1 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WGR1 
Go to UniProtKB:  P9WGR1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WGR1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAI
Query on NAI

Download Ideal Coordinates CCD File 
B [auth A]1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE
C21 H29 N7 O14 P2
BOPGDPNILDQYTO-NNYOXOHSSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.249 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.195 
  • Space Group: P 62 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 97.649α = 90
b = 97.649β = 90
c = 139.561γ = 120
Software Package:
Software NamePurpose
XDSdata scaling
PHASERphasing
REFMACrefinement
XDSdata reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-10-03
    Type: Initial release
  • Version 1.1: 2012-10-17
    Changes: Database references
  • Version 1.2: 2017-03-29
    Changes: Refinement description
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references, Derived calculations