2FJ0

Crystal Structure of Juvenile Hormone Esterase from Manduca sexta, with OTFP covalently attached

Summary for 2FJ0

• Entry DOI: 10.2210/pdb2fj0/pdb
• Descriptor: Carboxylic ester hydrolase, 1,1,1-TRIFLUORO-3-(OCTYLTHIO)ACETONE (3 entities in total)
• Functional Keywords: esterase, juvenile hormone, manduca sexta, alpha-beta hydrolase, hydrolase
• Biological source: Manduca sexta (Carolina sphinx,hornblower,tobacco hawkmoth,tomato hornworm)
• Total number of polymer chains: 1
• Total formula weight: 62411.57

Authors

Wogulis, M.,Wilson, D.K. (deposition date: 2005-12-30, release date: 2006-05-23, Last modification date: 2024-10-16)

Primary citation

Wogulis, M.,Wheelock, C.E.,Kamita, S.G.,Hinton, A.C.,Whetstone, P.A.,Hammock, B.D.,Wilson, D.K.
Structural studies of a potent insect maturation inhibitor bound to the juvenile hormone esterase of Manduca sexta.
Biochemistry, 45:4045-4057, 2006

PubMed 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.

PubMed: 16566578
DOI: 10.1021/bi0521644

Experimental method

X-RAY DIFFRACTION (2.7 Å)