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PDBsum entry 4dre

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protein ligands links
Oxidoreductase PDB id
4dre
Jmol
Contents
Protein chain
267 a.a.
Ligands
NAI
Waters ×38
PDB id:
4dre
Name: Oxidoreductase
Title: Mycobacterium tuberculosis inha in complex with nadh
Structure: Enoyl-[acyl-carrier-protein] reductase [nadh]. Chain: a. Synonym: nadh-dependent enoyl-acp reductase. Engineered: yes
Source: Mycobacterium tuberculosis. Organism_taxid: 1773. Strain: h37rv. Gene: inha, mt1531, mtcy277.05, rv1484. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.40Å     R-factor:   0.195     R-free:   0.249
Authors: F.Pojer,R.C.Hartkoorn,S.Boy,S.T.Cole
Key ref: R.C.Hartkoorn et al. (2012). Towards a new tuberculosis drug: pyridomycin - nature's isoniazid. EMBO Mol Med, 4, 1032-1042. PubMed id: 22987724
Date:
17-Feb-12     Release date:   03-Oct-12    
PROCHECK
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 Headers
 References

Protein chain
Pfam  
P9WGR1  (INHA_MYCTU) -  Enoyl-[acyl-carrier-protein] reductase [NADH]
Seq:
Struc:
269 a.a.
267 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(+)
= 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    
 
 
EMBO Mol Med 4:1032-1042 (2012)
PubMed id: 22987724  
 
 
Towards a new tuberculosis drug: pyridomycin - nature's isoniazid.
R.C.Hartkoorn, C.Sala, J.Neres, F.Pojer, S.Magnet, R.Mukherjee, S.Uplekar, S.Boy-Röttger, K.H.Altmann, S.T.Cole.
 
  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.