Wogulis_2006_Biochemistry_45_4045

Reference

Title : Structural studies of a potent insect maturation inhibitor bound to the juvenile hormone esterase of Manduca sexta - Wogulis_2006_Biochemistry_45_4045
Author(s) : Wogulis M , Wheelock CE , Kamita SG , Hinton AC , Whetstone PA , Hammock BD , Wilson DK
Ref : Biochemistry , 45 :4045 , 2006
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.

PubMedSearch : Wogulis_2006_Biochemistry_45_4045
PubMedID: 16566578
Gene_locus related to this paper: manse-jhest

Related information

Inhibitor OTFP
Substrate OTFP    HEPTAT
Gene_locus OTFP    HEPTAT    manse-jhest
Family OTFP    HEPTAT    manse-jhest    Juvenile_hormone_esterase
Structure OTFP    HEPTAT    manse-jhest    Juvenile_hormone_esterase    2FJ0

Citations formats

Wogulis M, Wheelock CE, Kamita SG, Hinton AC, Whetstone PA, Hammock BD, Wilson DK (2006)
Structural studies of a potent insect maturation inhibitor bound to the juvenile hormone esterase of Manduca sexta
Biochemistry 45 :4045

Wogulis M, Wheelock CE, Kamita SG, Hinton AC, Whetstone PA, Hammock BD, Wilson DK (2006)
Biochemistry 45 :4045