1zd5

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spinqualitylabelsall models 1zd5, resolution 2.6Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Human soluble epoxide hydrolase 4-(3-cyclohexyluriedo)-heptanoic acid complex

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

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 A, 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.

Disease

Known disease associated with this structure: Hypercholesterolemia, familial, due to LDLR defect, modifier of OMIM:[132811]

About this Structure

1ZD5 is a Single protein structure of sequence from Homo sapiens with MG, PO4 and NC7 as ligands. Active as Microsomal epoxide hydrolase, with EC number 3.3.2.9 Full crystallographic information is available from OCA.

Reference

Human soluble epoxide hydrolase: structural basis of inhibition by 4-(3-cyclohexylureido)-carboxylic acids., Gomez GA, Morisseau C, Hammock BD, Christianson DW, Protein Sci. 2006 Jan;15(1):58-64. Epub 2005 Dec 1. PMID:16322563

Page seeded by OCA on Mon Nov 12 20:32:45 2007