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 language | English (US) |
|---|---|
| Pages (from-to) | 58-64 |
| Number of pages | 7 |
| Journal | Protein Science |
| Volume | 15 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2006 |
Fingerprint
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 journal › Article
}
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 -