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PDBsum entry 3fnh

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protein ligands links
Oxidoreductase PDB id
3fnh
Jmol
Contents
Protein chain
268 a.a. *
Ligands
NAD
JPJ
Waters ×11
* Residue conservation analysis
PDB id:
3fnh
Name: Oxidoreductase
Title: Crystal structure of inha bound to triclosan derivative
Structure: Enoyl-[acyl-carrier-protein] reductase [nadh]. Chain: a. Synonym: nadh-dependent enoyl-acp reductase. Engineered: yes
Source: Mycobacterium tuberculosis. Organism_taxid: 1773. Gene: inha, rv1484, mt1531, mtcy277.05. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.80Å     R-factor:   0.223     R-free:   0.268
Authors: F.Wang
Key ref: J.S.Freundlich et al. (2009). Triclosan derivatives: towards potent inhibitors of drug-sensitive and drug-resistant Mycobacterium tuberculosis. ChemMedChem, 4, 241-248. PubMed id: 19130456
Date:
24-Dec-08     Release date:   20-Jan-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam  
P9WGR1  (INHA_MYCTU) -  Enoyl-[acyl-carrier-protein] reductase [NADH]
Seq:
Struc:
269 a.a.
268 a.a.
Key:    Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.1.3.1.9  - Enoyl-[acyl-carrier-protein] reductase (NADH).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: An acyl-[acyl-carrier protein] + NAD+ = a trans-2,3-dehydroacyl-[acyl- carrier protein] + NADH
acyl-[acyl-carrier protein]
+
NAD(+)
Bound ligand (Het Group name = NAD)
corresponds exactly
= trans-2,3-dehydroacyl-[acyl- carrier protein]
+ NADH
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     oxidation-reduction process   5 terms 
  Biochemical function     oxidoreductase activity     2 terms  

 

 
    reference    
 
 
ChemMedChem 4:241-248 (2009)
PubMed id: 19130456  
 
 
Triclosan derivatives: towards potent inhibitors of drug-sensitive and drug-resistant Mycobacterium tuberculosis.
J.S.Freundlich, F.Wang, C.Vilchèze, G.Gulten, R.Langley, G.A.Schiehser, D.P.Jacobus, W.R.Jacobs, J.C.Sacchettini.
 
  ABSTRACT  
 
Triclosan has been previously shown to inhibit InhA, an essential enoyl acyl carrier protein reductase involved in mycolic acid biosynthesis, the inhibition of which leads to the lysis of Mycobacterium tuberculosis. Using a structure-based drug design approach, a series of 5-substituted triclosan derivatives was developed. Two groups of derivatives with alkyl and aryl substituents, respectively, were identified with dramatically enhanced potency against purified InhA. The most efficacious inhibitor displayed an IC(50) value of 21 nM, which was 50-fold more potent than triclosan. X-ray crystal structures of InhA in complex with four triclosan derivatives revealed the structural basis for the inhibitory activity. Six selected triclosan derivatives were tested against isoniazid-sensitive and resistant strains of M. tuberculosis. Among those, the best inhibitor had an MIC value of 4.7 microg mL(-1) (13 microM), which represents a tenfold improvement over the bacteriocidal activity of triclosan. A subset of these triclosan analogues was more potent than isoniazid against two isoniazid-resistant M. tuberculosis strains, demonstrating the significant potential for structure-based design in the development of next generation antitubercular drugs.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21365086 E.Parisini, P.Metrangolo, T.Pilati, G.Resnati, and G.Terraneo (2011).
Halogen bonding in halocarbon-protein complexes: a structural survey.
  Chem Soc Rev, 40, 2267-2278.  
20158608 A.Gurvitz (2010).
Triclosan inhibition of mycobacterial InhA in Saccharomyces cerevisiae: yeast mitochondria as a novel platform for in vivo antimycolate assays.
  Lett Appl Microbiol, 50, 399-405.  
21143326 V.Molle, G.Gulten, C.Vilchèze, R.Veyron-Churlet, I.Zanella-Cléon, J.C.Sacchettini, W.R.Jacobs, and L.Kremer (2010).
Phosphorylation of InhA inhibits mycolic acid biosynthesis and growth of Mycobacterium tuberculosis.
  Mol Microbiol, 78, 1591-1605.
PDB codes: 3oew 3oey 3of2
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