RCSB PDB - 2IEB: Crystal Structure of Isoniazid-resistant S94A ENOYL-ACP(COA) Reductase Mutant Enzyme from MYCOBACTERIUM TUBERCULOSIS in Complex with NADH-INH

 2IEB

Crystal Structure of Isoniazid-resistant S94A ENOYL-ACP(COA) Reductase Mutant Enzyme from MYCOBACTERIUM TUBERCULOSIS in Complex with NADH-INH


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.187 

Starting Model: experimental
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Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted ZIDClick on this verticalbar to view details

This is version 1.4 of the entry. See complete history


Literature

Crystallographic studies on the binding of isonicotinyl-NAD adduct to wild-type and isoniazid resistant 2-trans-enoyl-ACP (CoA) reductase from Mycobacterium tuberculosis.

Dias, M.V.Vasconcelos, I.B.Prado, A.M.Fadel, V.Basso, L.A.de Azevedo, W.F.Santos, D.S.

(2007) J Struct Biol 159: 369-380

  • DOI: https://doi.org/10.1016/j.jsb.2007.04.009
  • Primary Citation of Related Structures:  
    2IDZ, 2IE0, 2IEB, 2IED

  • PubMed Abstract: 

    The resumption of tuberculosis led to an increased need to understand the molecular mechanisms of drug action and drug resistance, which should provide significant insight into the development of newer compounds. Isoniazid (INH), the most prescribed drug to treat TB, inhibits an NADH-dependent enoyl-acyl carrier protein reductase (InhA) that provides precursors of mycolic acids, which are components of the mycobacterial cell wall. InhA is the major target of the mode of action of isoniazid. INH is a pro-drug that needs activation to form the inhibitory INH-NAD adduct. Missense mutations in the inhA structural gene have been identified in clinical isolates of Mycobacterium tuberculosis resistant to INH. To understand the mechanism of resistance to INH, we have solved the structure of two InhA mutants (I21V and S94A), identified in INH-resistant clinical isolates, and compare them to INH-sensitive WT InhA structure in complex with the INH-NAD adduct. We also solved the structure of unliganded INH-resistant S94A protein, which is the first report on apo form of InhA. The salient features of these structures are discussed and should provide structural information to improve our understanding of the mechanism of action of, and resistance to, INH in M. tuberculosis. The unliganded structure of InhA allows identification of conformational changes upon ligand binding and should help structure-based drug design of more potent antimycobacterial agents.


  • Organizational Affiliation

    Programa de Pós-Graduação em Biofísica Molecular-Departamento de Física, UNESP, São José do Rio Preto, SP 15054-000, Brazil.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Enoyl-[acyl-carrier-protein] reductase [NADH]268Mycobacterium tuberculosisMutation(s): 1 
Gene Names: inhA
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
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ZID
Query on ZID

Download Ideal Coordinates CCD File 
B [auth A]ISONICOTINIC-ACETYL-NICOTINAMIDE-ADENINE DINUCLEOTIDE
C27 H30 N8 O15 P2
SURAWYIAXPVHGO-XDBKRARRSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.187 
  • Space Group: P 62 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 96.83α = 90
b = 96.83β = 90
c = 136.418γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
MAR345dtbdata collection
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing

Structure Validation

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Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted ZIDClick on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-07-24
    Type: Initial release
  • Version 1.1: 2007-10-03
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Derived calculations, Version format compliance
  • Version 1.3: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.4: 2023-08-30
    Changes: Data collection, Refinement description