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PDBsum entry 2jjy

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protein ligands Protein-protein interface(s) links
Oxidoreductase PDB id
2jjy
Jmol
Contents
Protein chains
256 a.a. *
Ligands
NAD
* Residue conservation analysis
PDB id:
2jjy
Name: Oxidoreductase
Title: Crystal structure of francisella tularensis enoyl reductase (ftfabi) with bound NAD
Structure: Enoyl-[acyl-carrier-protein] reductase. Chain: a, b, c, d. Synonym: enoyl reductase, nadh. Other_details: 6xhistidine at c-terminus
Source: Francisella tularensis. Organism_taxid: 263
Resolution:
2.90Å     R-factor:   0.206     R-free:   0.281
Authors: S.R.Luckner,H.Lu,J.J.Truglio,P.J.Tonge,C.Kisker
Key ref: H.Lu et al. (2009). Slow-onset inhibition of the FabI enoyl reductase from francisella tularensis: residence time and in vivo activity. ACS Chem Biol, 4, 221-231. PubMed id: 19206187
Date:
25-Apr-08     Release date:   24-Feb-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q14I55  (Q14I55_FRAT1) -  Enoyl-[acyl-carrier-protein] reductase [NADH]
Seq:
Struc:
260 a.a.
256 a.a.
Key:    PfamA domain  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     metabolic process   3 terms 
  Biochemical function     nucleotide binding     3 terms  

 

 
    reference    
 
 
ACS Chem Biol 4:221-231 (2009)
PubMed id: 19206187  
 
 
Slow-onset inhibition of the FabI enoyl reductase from francisella tularensis: residence time and in vivo activity.
H.Lu, K.England, C.am Ende, J.J.Truglio, S.Luckner, B.G.Reddy, N.L.Marlenee, S.E.Knudson, D.L.Knudson, R.A.Bowen, C.Kisker, R.A.Slayden, P.J.Tonge.
 
  ABSTRACT  
 
Francisella tularensis is a highly virulent and contagious Gram-negative intracellular bacterium that causes the disease tularemia in mammals. The high infectivity and the ability of the bacterium to survive for weeks in a cool, moist environment have raised the possibility that this organism could be exploited deliberately as a potential biological weapon. Fatty acid biosynthesis (FAS-II) is essential for bacterial viability and has been validated as a target for the discovery of novel antibacterials. The FAS-II enoyl reductase ftuFabI has been cloned and expressed, and a series of diphenyl ethers have been identified that are subnanomolar inhibitors of the enzyme with MIC90 values as low as 0.00018 microg mL(-1). The existence of a linear correlation between the Ki and MIC values strongly suggests that the antibacterial activity of the diphenyl ethers results from direct inhibition of ftuFabI within the cell. The compounds are slow-onset inhibitors of ftuFabI, and the residence time of the inhibitors on the enzyme correlates with their in vivo activity in a mouse model of tularemia infection. Significantly, the rate of breakdown of the enzyme-inhibitor complex is a better predictor of in vivo activity than the overall thermodynamic stability of the complex, a concept that has important implications for the discovery of novel chemotherapeutics that normally rely on equilibrium measurements of potency.
 

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.  
20018879 C.A.Machutta, G.R.Bommineni, S.R.Luckner, K.Kapilashrami, B.Ruzsicska, C.Simmerling, C.Kisker, and P.J.Tonge (2010).
Slow onset inhibition of bacterial beta-ketoacyl-acyl carrier protein synthases by thiolactomycin.
  J Biol Chem, 285, 6161-6169.  
20055482 H.Lu, and P.J.Tonge (2010).
Mechanism and inhibition of the FabV enoyl-ACP reductase from Burkholderia mallei.
  Biochemistry, 49, 1281-1289.  
19734171 K.England, C.am Ende, H.Lu, T.J.Sullivan, N.L.Marlenee, R.A.Bowen, S.E.Knudson, D.L.Knudson, P.J.Tonge, and R.A.Slayden (2009).
Substituted diphenyl ethers as a broad-spectrum platform for the development of chemotherapeutics for the treatment of tularaemia.
  J Antimicrob Chemother, 64, 1052-1061.  
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.