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PDBsum entry 2fj0

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protein ligands links
Hydrolase PDB id
2fj0
Jmol
Contents
Protein chain
530 a.a. *
Ligands
TFC
Waters ×101
* Residue conservation analysis
PDB id:
2fj0
Name: Hydrolase
Title: Crystal structure of juvenile hormone esterase from manduca sexta, with otfp covalently attached
Structure: Juvenile hormone esterase. Chain: a. Engineered: yes
Source: Trichoplusia ni. Cabbage looper. Organism_taxid: 7111. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469
Resolution:
2.70Å     R-factor:   0.204     R-free:   0.251
Authors: M.Wogulis,D.K.Wilson
Key ref:
M.Wogulis et al. (2006). Structural studies of a potent insect maturation inhibitor bound to the juvenile hormone esterase of Manduca sexta. Biochemistry, 45, 4045-4057. PubMed id: 16566578 DOI: 10.1021/bi0521644
Date:
30-Dec-05     Release date:   23-May-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9GPG0  (Q9GPG0_MANSE) -  Juvenile hormone esterase
Seq:
Struc:
 
Seq:
Struc:
573 a.a.
530 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     metabolic process   1 term 
  Biochemical function     hydrolase activity     1 term  

 

 
DOI no: 10.1021/bi0521644 Biochemistry 45:4045-4057 (2006)
PubMed id: 16566578  
 
 
Structural studies of a potent insect maturation inhibitor bound to the juvenile hormone esterase of Manduca sexta.
M.Wogulis, C.E.Wheelock, S.G.Kamita, A.C.Hinton, P.A.Whetstone, B.D.Hammock, D.K.Wilson.
 
  ABSTRACT  
 
Juvenile hormone (JH) is an insect hormone containing an alpha,beta-unsaturated ester consisting of a small alcohol and long, hydrophobic acid. JH degradation is required for proper insect development. One pathway of this degradation is through juvenile hormone esterase (JHE), which cleaves the JH ester bond to produce methanol and JH acid. JHE is a member of the functionally divergent alpha/beta-hydrolase family of enzymes and is a highly efficient enzyme that cleaves JH at very low in vivo concentrations. We present here a 2.7 A crystal structure of JHE from the tobacco hornworm Manduca sexta (MsJHE) in complex with the transition state analogue inhibitor 3-octylthio-1,1,1-trifluoropropan-2-one (OTFP) covalently bound to the active site. This crystal structure, the first JHE structure reported, contains a long, hydrophobic binding pocket with the solvent-inaccessible catalytic triad located at the end. The structure explains many of the interactions observed between JHE and its substrates and inhibitors, such as the preference for small alcohol groups and long hydrophobic backbones. The most potent JHE inhibitors identified to date contain a trifluoromethyl ketone (TFK) moiety and have a sulfur atom beta to the ketone. In this study, sulfur-aromatic interactions were observed between the sulfur atom of OTFP and a conserved aromatic residue in the crystal structure. Mutational analysis supported the hypothesis that these interactions contribute to the potency of sulfur-containing TFK inhibitors. Together, these results clarify the binding mechanism of JHE inhibitors and provide useful observations for the development of additional enzyme inhibitors for a variety of enzymes.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20676708 J.Rayo, L.Muñoz, G.Rosell, B.D.Hammock, A.Guerrero, F.J.Luque, and R.Pouplana (2010).
Reactivity versus steric effects in fluorinated ketones as esterase inhibitors: a quantum mechanical and molecular dynamics study.
  J Mol Model, 16, 1753-1764.  
21071843 T.Tsubota, T.Nakakura, T.Shinoda, and T.Shiotsuki (2010).
Characterization and analysis of novel carboxyl/cholinesterase genes possessing the Thr-316 motif in the silkworm, Bombyx mori.
  Biosci Biotechnol Biochem, 74, 2259-2266.  
19301127 A.A.Bernardo, and H.E.Bicudo (2009).
Variability of esterase patterns in adult flies of the saltans species group of Drosophila (subgenus Sophophora).
  Genetica, 137, 111-124.  
19062296 T.Harada, Y.Nakagawa, R.M.Wadkins, P.M.Potter, and C.E.Wheelock (2009).
Comparison of benzil and trifluoromethyl ketone (TFK)-mediated carboxylesterase inhibition using classical and 3D-quantitative structure-activity relationship analysis.
  Bioorg Med Chem, 17, 149-164.  
18023188 C.E.Wheelock, K.Nishi, A.Ying, P.D.Jones, M.E.Colvin, M.M.Olmstead, and B.D.Hammock (2008).
Influence of sulfur oxidation state and steric bulk upon trifluoromethyl ketone (TFK) binding kinetics to carboxylesterases and fatty acid amide hydrolase (FAAH).
  Bioorg Med Chem, 16, 2114-2130.  
17628281 H.Bai, P.Ramaseshadri, and S.R.Palli (2007).
Identification and characterization of juvenile hormone esterase gene from the yellow fever mosquito, Aedes aegypti.
  Insect Biochem Mol Biol, 37, 829-837.  
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.