15-deoxy-Δ12,14-Prostaglandin J2 inhibits human soluble epoxide hydrolase by a dual orthosteric and allosteric mechanism.
PMID 31123712 · Communications biology · 2019 · DOI 10.1038/s42003-019-0426-2
Authors: Giancarlo Abis; Rebecca L Charles; Jolanta Kopec; Wyatt W Yue; R Andrew Atkinson; Tam T T Bui; Steven Lynham; Simona Popova; Yin-Biao Sun; Franca Fraternali; Philip Eaton; Maria R Conte
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.
Allosteric Regulation; Amino Acid Sequence; Amino Acid Substitution; Catalytic Domain; Crystallography, X-Ray; Cysteine; Enzyme Inhibitors; Enzyme Stability; Epoxide Hydrolases; Humans; Magnetic Resonance Spectroscopy; Models, Molecular; Mutagenesis, Site-Directed; Prostaglandin D2; Protein Domains; Sequence Alignment; Solubility
Cite
Giancarlo Abis; Rebecca L Charles; Jolanta Kopec; Wyatt W Yue; R Andrew Atkinson; Tam T T Bui; Steven Lynham; Simona Popova; Yin-Biao Sun; Franca Fraternali; Philip Eaton; Maria R Conte. 15-deoxy-Δ12,14-Prostaglandin J2 inhibits human soluble epoxide hydrolase by a dual orthosteric and allosteric mechanism. Communications biology (2019). PMID 31123712. DOI 10.1038/s42003-019-0426-2.