1ZD4: Human Soluble Epoxide Hydrolase 4-(3-cyclohexyluriedo)- Hexanoic Acid Complex

Citation:
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 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.
PDB ID: 1ZD4Download
MMDB ID: 37931
PDB Deposition Date: 2005/4/14
Updated in MMDB: 2012/10 
Experimental Method:
x-ray diffraction
Resolution: 2.7  Å
Source Organism:
Similar Structures:
Biological Unit for 1ZD4: dimeric; determined by author
Molecular Components in 1ZD4
Label Count Molecule
Proteins (2 molecules)
2
Epoxide Hydrolase 2, Cytoplasmic
Molecule annotation
Chemicals (6 molecules)
1
2
2
2
3
2
* Click molecule labels to explore molecular sequence information.

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