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PDBsum entry 2x23

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
2x23
Jmol
Contents
Protein chains
268 a.a. *
Ligands
NAD ×4
TCU ×4
DMS
Waters ×682
* Residue conservation analysis
PDB id:
2x23
Name: Oxidoreductase
Title: Crystal structure of m. Tuberculosis inha inhibited by pt70
Structure: Enoyl-[acyl-carrier-protein] reductase [nadh]. Chain: a, b, e, g. Synonym: nadh-dependent enoyl-acp reductase, enoyl reductas engineered: yes
Source: Mycobacterium tuberculosis. Organism_taxid: 83332. Strain: h37rv. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: plyss
Resolution:
1.81Å     R-factor:   0.169     R-free:   0.203
Authors: S.R.Luckner,N.Liu,C.W.Am Ende,P.J.Tonge,C.Kisker
Key ref: S.R.Luckner et al. (2010). A slow, tight binding inhibitor of InhA, the enoyl-acyl carrier protein reductase from Mycobacterium tuberculosis. J Biol Chem, 285, 14330-14337. PubMed id: 20200152 DOI: 10.1074/jbc.M109.090373
Date:
10-Jan-10     Release date:   02-Mar-10    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
No UniProt id for this chain
Struc: 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!
  Cellular component     cell wall   2 terms 
  Biological process     mycolic acid biosynthetic process   7 terms 
  Biochemical function     oxidoreductase activity     4 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M109.090373 J Biol Chem 285:14330-14337 (2010)
PubMed id: 20200152  
 
 
A slow, tight binding inhibitor of InhA, the enoyl-acyl carrier protein reductase from Mycobacterium tuberculosis.
S.R.Luckner, N.Liu, C.W.am Ende, P.J.Tonge, C.Kisker.
 
  ABSTRACT  
 
InhA, the enoyl-ACP reductase in Mycobacterium tuberculosis is an attractive target for the development of novel drugs against tuberculosis, a disease that kills more than two million people each year. InhA is the target of the current first line drug isoniazid for the treatment of tuberculosis infections. Compounds that directly target InhA and do not require activation by the mycobacterial catalase-peroxidase KatG are promising candidates for treating infections caused by isoniazid-resistant strains. Previously we reported the synthesis of several diphenyl ethers with nanomolar affinity for InhA. However, these compounds are rapid reversible inhibitors of the enzyme, and based on the knowledge that long drug target residence times are an important factor for in vivo drug activity, we set out to generate a slow onset inhibitor of InhA using structure-based drug design. 2-(o-Tolyloxy)-5-hexylphenol (PT70) is a slow, tight binding inhibitor of InhA with a K(1) value of 22 pm. PT70 binds preferentially to the InhA x NAD(+) complex and has a residence time of 24 min on the target, which is 14,000 times longer than that of the rapid reversible inhibitor from which it is derived. The 1.8 A crystal structure of the ternary complex between InhA, NAD(+), and PT70 reveals the molecular details of enzyme-inhibitor recognition and supports the hypothesis that slow onset inhibition is coupled to ordering of an active site loop, which leads to the closure of the substrate-binding pocket.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21393229 N.Liu, J.E.Cummings, K.England, R.A.Slayden, and P.J.Tonge (2011).
Mechanism and inhibition of the FabI enoyl-ACP reductase from Burkholderia pseudomallei.
  J Antimicrob Chemother, 66, 564-573.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.