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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
Diamond Keywords: Enzymes
Subject Areas:
Biology and Bio-materials,
Medicine,
Chemistry
Instruments:
I02-Macromolecular Crystallography
,
I04-Macromolecular Crystallography
Added On:
28/05/2019 14:34
Documents:
s42003-019-0426-2.pdf
Discipline Tags:
Health & Wellbeing
Biochemistry
Chemistry
Structural biology
Biophysics
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)