2fj0
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Crystal Structure of Juvenile Hormone Esterase from Manduca sexta, with OTFP covalently attached
OverviewOverview
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.
About this StructureAbout this Structure
2FJ0 is a Single protein structure of sequence from Trichoplusia ni with as ligand. Active as Carboxylesterase, with EC number 3.1.1.1 Full crystallographic information is available from OCA.
ReferenceReference
Structural studies of a potent insect maturation inhibitor bound to the juvenile hormone esterase of Manduca sexta., Wogulis M, Wheelock CE, Kamita SG, Hinton AC, Whetstone PA, Hammock BD, Wilson DK, Biochemistry. 2006 Apr 4;45(13):4045-57. PMID:16566578
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