RCSB PDB - 1W6F: Arylamine N-acetyltransferase from Mycobacterium smegmatis with the anti-tubercular drug isoniazid bound in the active site.

 1W6F

Arylamine N-acetyltransferase from Mycobacterium smegmatis with the anti-tubercular drug isoniazid bound in the active site.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 

Starting Model: experimental
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This is version 1.3 of the entry. See complete history


Literature

Binding of the Anti-Tubercular Drug Isoniazid to the Arylamine N-Acetyltransferase Protein from Mycobacterium Smegmatis

Sandy, J.Holton, S.Fullham, E.Sim, E.Noble, M.E.M.

(2005) Protein Sci 14: 775

  • DOI: https://doi.org/10.1110/ps.041163505
  • Primary Citation of Related Structures:  
    1W6F

  • PubMed Abstract: 

    Isoniazid is a frontline drug used in the treatment of tuberculosis (TB). Isoniazid is a prodrug, requiring activation in the mycobacterial cell by the catalase/peroxidase activity of the katG gene product. TB kills two million people every year and the situation is getting worse due to the increase in prevalence of HIV/AIDS and emergence of multidrug-resistant strains of TB. Arylamine N-acetyltransferase (NAT) is a drug-metabolizing enzyme (E.C. 2.1.3.5). NAT can acetylate isoniazid, transferring an acetyl group from acetyl coenzyme A onto the terminal nitrogen of the drug, which in its N-acetylated form is therapeutically inactive. The bacterium responsible for TB, Mycobacterium tuberculosis, contains and expresses the gene encoding the NAT protein. Isoniazid binds to the NAT protein from Salmonella typhimurium and we report here the mode of binding of isoniazid in the NAT enzyme from Mycobacterium smegmatis, closely related to the M. tuberculosis and S. typhimurium NAT enzymes. The mode of binding of isoniazid to M. smegmatis NAT has been determined using data collected from two distinct crystal forms. We can say with confidence that the observed mode of binding of isoniazid is not an artifact of the crystallization conditions used. The NAT enzyme is active in mycobacterial cells and we propose that isoniazid binds to the NAT enzyme in these cells. NAT activity in M. tuberculosis is likely therefore to modulate the degree of activation of isoniazid by other enzymes within the mycobacterial cell. The structure of NAT with isoniazid bound will facilitate rational drug design for anti-tubercular therapy.


  • Organizational Affiliation

    Department of Pharmacology, Oxford University, Mansfield Road, Oxford, OX1 3QT, United Kingdom. james.sandy@pharm.ox.ac.uk


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ARYLAMINE N-ACETYLTRANSFERASE
A, B, C, D
278Mycolicibacterium smegmatisMutation(s): 0 
EC: 2.3.1.5
UniProt
Find proteins for O86309 (Mycolicibacterium smegmatis)
Explore O86309 
Go to UniProtKB:  O86309
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO86309
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 101.208α = 90
b = 106.039β = 90
c = 140.362γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2005-02-23
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-12-13
    Changes: Data collection, Database references, Other, Refinement description