Human soluble epoxide hydrolase: Structural basis of inhibition by 4-(3-cyclohexylureido)-carboxylic acids

German A. Gomez, Christophe Morisseau, Bruce D. Hammock, David W. Christianson

Research output: Contribution to journalArticle

72 Citations (Scopus)

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. Published by Cold Spring Harbor Laboratory Press.

Original languageEnglish (US)
Pages (from-to)58-64
Number of pages7
JournalProtein Science
Volume15
Issue number1
DOIs
StatePublished - Jan 2006

Fingerprint

Epoxide Hydrolases
Carboxylic Acids
Epoxy Compounds
Bearings (structural)
Substrates
Ports and harbors
Tail
Catalytic Domain
Tunnels
Screening
Carbon
Crystal structure
X-Rays
Hypertension
X rays
Acids

Keywords

  • Domain swapped dimer
  • Epoxide hydrolase
  • Inhibition

ASJC Scopus subject areas

  • Biochemistry

Cite this

Human soluble epoxide hydrolase : Structural basis of inhibition by 4-(3-cyclohexylureido)-carboxylic acids. / Gomez, German A.; Morisseau, Christophe; Hammock, Bruce D.; Christianson, David W.

In: Protein Science, Vol. 15, No. 1, 01.2006, p. 58-64.

Research output: Contribution to journalArticle

Gomez, German A. ; Morisseau, Christophe ; Hammock, Bruce D. ; Christianson, David W. / Human soluble epoxide hydrolase : Structural basis of inhibition by 4-(3-cyclohexylureido)-carboxylic acids. In: Protein Science. 2006 ; Vol. 15, No. 1. pp. 58-64.
@article{be22ac393d5d48af95e47d8b07cdd7c2,
title = "Human soluble epoxide hydrolase: Structural basis of inhibition by 4-(3-cyclohexylureido)-carboxylic acids",
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 {\AA} 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. Published by Cold Spring Harbor Laboratory Press.",
keywords = "Domain swapped dimer, Epoxide hydrolase, Inhibition",
author = "Gomez, {German A.} and Christophe Morisseau and Hammock, {Bruce D.} and Christianson, {David W.}",
year = "2006",
month = "1",
doi = "10.1110/ps.051720206",
language = "English (US)",
volume = "15",
pages = "58--64",
journal = "Protein Science",
issn = "0961-8368",
publisher = "Cold Spring Harbor Laboratory Press",
number = "1",

}

TY - JOUR

T1 - Human soluble epoxide hydrolase

T2 - Structural basis of inhibition by 4-(3-cyclohexylureido)-carboxylic acids

AU - Gomez, German A.

AU - Morisseau, Christophe

AU - Hammock, Bruce D.

AU - Christianson, David W.

PY - 2006/1

Y1 - 2006/1

N2 - 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. Published by Cold Spring Harbor Laboratory Press.

AB - 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. Published by Cold Spring Harbor Laboratory Press.

KW - Domain swapped dimer

KW - Epoxide hydrolase

KW - Inhibition

UR - http://www.scopus.com/inward/record.url?scp=29344455172&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=29344455172&partnerID=8YFLogxK

U2 - 10.1110/ps.051720206

DO - 10.1110/ps.051720206

M3 - Article

C2 - 16322563

AN - SCOPUS:29344455172

VL - 15

SP - 58

EP - 64

JO - Protein Science

JF - Protein Science

SN - 0961-8368

IS - 1

ER -