Human soluble epoxide hydrolase: Structural basis of inhibition by 4‐(3‐cyclohexylureido)‐carboxylic acids
Open Access
- 1 January 2006
- journal article
- Published by Wiley in Protein Science
- Vol. 15 (1), 58-64
- https://doi.org/10.1110/ps.051720206
Abstract
X‐ray crystal structures of human soluble epoxide hydrolase (sEH) complexed with four different dialkylurea inhibitors bearing pendant carboxylate “tails” of varying length have been determined at 2.3–3.0 Å resolution. Similarities among inhibitor binding modes reinforce the proposed roles of Y381 and/or Y465 as general acids that protonate the epoxide ring of the substrate in concert with nucleophilic attack of D333 at the electrophilic epoxide carbon. Additionally, the binding of these inhibitors allows us to model the binding mode of the endogenous substrate 14,15‐epoxyeicosatrienoic acid. Contrasts among inhibitor binding modes include opposite orientations of inhibitor binding in the active‐site hydrophobic tunnel. Alternative binding orientations observed for this series of inhibitors to human sEH, as well as the binding of certain dialkylurea inhibitors to human sEH and murine sEH, complicate the structure‐based design of human sEH inhibitors with potential pharmaceutical applications in the treatment of hypertension. Thus, with regard to the optimization of inhibitor designs targeting human sEH, it is critical that human sEH and not murine sEH be utilized for inhibitor screening, and it is critical that structures of human sEH‐inhibitor complexes be determined to verify inhibitor binding orientations that correlate with measured affinities.Keywords
This publication has 38 references indexed in Scilit:
- Pathways of Epoxyeicosatrienoic Acid Metabolism in Endothelial CellsJournal of Biological Chemistry, 2001
- Biochemical Evidence for the Involvement of Tyrosine in Epoxide Activation during the Catalytic Cycle of Epoxide HydrolaseJournal of Biological Chemistry, 2000
- Mechanism of Microsomal Epoxide Hydrolase. Semifunctional Site-Specific Mutants Affecting the Alkylation Half-ReactionBiochemistry, 1998
- [20] Processing of X-ray diffraction data collected in oscillation modeMethods in Enzymology, 1997
- Mechanism of Soluble Epoxide HydrolaseJournal of Biological Chemistry, 1995
- Role of Cytochrome P-450 Enzymes and Metabolites of Arachidonic Acid in the Control of Vascular ToneJournal of Vascular Research, 1995
- AMoRe: an automated package for molecular replacementActa Crystallographica Section A Foundations of Crystallography, 1994
- Isolation of a Putative Hydroxyacyl Enzyme Intermediate of an Epoxide HydrolaseBiochemical and Biophysical Research Communications, 1994
- MOLSCRIPT: a program to produce both detailed and schematic plots of protein structuresJournal of Applied Crystallography, 1991
- Improved methods for building protein models in electron density maps and the location of errors in these modelsActa Crystallographica Section A Foundations of Crystallography, 1991