15-deoxy-Δ12,14-Prostaglandin J2 inhibits human soluble epoxide hydrolase by a dual orthosteric and allosteric mechanism

DOI: 10.1038/s42003-019-0426-2

Authors: Giancarlo Abis (King's College London) , Rebecca L. Charles (King’s College London) , Jolanta Kopec (Structural Genomics Consortium, University of Oxford) , Wyatt W. Yue (University of Oxford) , R. Andrew Atkinson (King’s College London) , Tam T. T. Bui (King’s College London) , Steven Lynham (King’s College London) , Simona Popova (King’s College London) , Yin-biao Sun (King’s College London) , Franca Fraternali (King’s College London) , Philip Eaton (King’s College London) , Maria R. Conte (King's College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Communications Biology , VOL 2

State: Published (Approved)
Published: May 2019
Diamond Proposal Number(s): 13597 , 10619

Abstract: Human soluble epoxide hydrolase (hsEH) is an enzyme responsible for the inactivation of bioactive epoxy fatty acids, and its inhibition is emerging as a promising therapeutical strategy to target hypertension, cardiovascular disease, pain and insulin sensitivity. Here, we uncover the molecular bases of hsEH inhibition mediated by the endogenous 15-deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2). Our data reveal a dual inhibitory mechanism, whereby hsEH can be inhibited by reversible docking of 15d-PGJ2 in the catalytic pocket, as well as by covalent locking of the same compound onto cysteine residues C423 and C522, remote to the active site. Biophysical characterisations allied with in silico investigations indicate that the covalent modification of the reactive cysteines may be part of a hitherto undiscovered allosteric regulatory mechanism of the enzyme. This study provides insights into the molecular modes of inhibition of hsEH epoxy-hydrolytic activity and paves the way for the development of new allosteric inhibitors.

Journal Keywords: Molecular biophysics; X-ray crystallography

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography

Documents:
s42003-019-0426-2.pdf