PMID- 16322563
OWN - NLM
STAT- MEDLINE
DCOM- 20060323
LR  - 20181220
IS  - 0961-8368 (Print)
IS  - 1469-896X (Electronic)
IS  - 0961-8368 (Linking)
VI  - 15
IP  - 1
DP  - 2006 Jan
TI  - Human soluble epoxide hydrolase: structural basis of inhibition by 
      4-(3-cyclohexylureido)-carboxylic acids.
PG  - 58-64
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 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.
FAU - Gomez, German A
AU  - Gomez GA
AD  - Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, 
      USA.
FAU - Morisseau, Christophe
AU  - Morisseau C
FAU - Hammock, Bruce D
AU  - Hammock BD
FAU - Christianson, David W
AU  - Christianson DW
LA  - eng
SI  - PDB/1ZD2
SI  - PDB/1ZD3
SI  - PDB/1ZD4
SI  - PDB/1ZD5
GR  - GM63106/GM/NIGMS NIH HHS/United States
GR  - P30 ES05707/ES/NIEHS NIH HHS/United States
GR  - P30 ES005707/ES/NIEHS NIH HHS/United States
GR  - P42 ES004699/ES/NIEHS NIH HHS/United States
GR  - P42 ES04699/ES/NIEHS NIH HHS/United States
GR  - R01 GM063106/GM/NIGMS NIH HHS/United States
GR  - R37 ES02710/ES/NIEHS NIH HHS/United States
GR  - R37 ES002710/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20051201
PL  - United States
TA  - Protein Sci
JT  - Protein science : a publication of the Protein Society
JID - 9211750
RN  - 0 (Arachidonic Acids)
RN  - 0 (Carboxylic Acids)
RN  - 0 (Enzyme Inhibitors)
RN  - EC 3.3.2.- (Epoxide Hydrolases)
SB  - IM
MH  - Animals
MH  - Arachidonic Acids/chemistry/pharmacology
MH  - Binding Sites/physiology
MH  - Carboxylic Acids/*chemistry/pharmacology
MH  - Crystallography, X-Ray
MH  - Enzyme Inhibitors/*chemistry
MH  - Epoxide Hydrolases/*antagonists & inhibitors/*chemistry
MH  - Humans
MH  - Mice
MH  - Models, Molecular
MH  - Protein Binding/physiology
MH  - Protein Structure, Tertiary
MH  - *Quantitative Structure-Activity Relationship
MH  - Solubility
PMC - PMC1762130
MID - NIHMS7956
EDAT- 2005/12/03 09:00
MHDA- 2006/03/24 09:00
PMCR- 2007/01/01
CRDT- 2005/12/03 09:00
PHST- 2005/12/03 09:00 [pubmed]
PHST- 2006/03/24 09:00 [medline]
PHST- 2005/12/03 09:00 [entrez]
PHST- 2007/01/01 00:00 [pmc-release]
AID - ps.051720206 [pii]
AID - 0150058 [pii]
AID - 10.1110/ps.051720206 [doi]
PST - ppublish
SO  - Protein Sci. 2006 Jan;15(1):58-64. doi: 10.1110/ps.051720206. Epub 2005 Dec 1.