PDBsum entry 1zd4

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Hydrolase PDB id
Protein chain
547 a.a. *
Waters ×42
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Human soluble epoxide hydrolase 4-(3-cyclohexyluriedo)- hexanoic acid complex
Structure: Epoxide hydrolase 2, cytoplasmic. Chain: a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ephx2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
2.70Å     R-factor:   0.233     R-free:   0.283
Authors: G.A.Gomez,C.Morisseau,B.D.Hammock,D.W.Christianson
Key ref:
G.A.Gomez et al. (2006). Human soluble epoxide hydrolase: structural basis of inhibition by 4-(3-cyclohexylureido)-carboxylic acids. Protein Sci, 15, 58-64. PubMed id: 16322563 DOI: 10.1110/ps.051720206
14-Apr-05     Release date:   07-Mar-06    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P34913  (HYES_HUMAN) -  Bifunctional epoxide hydrolase 2
555 a.a.
547 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class 2: E.C.  - Lipid-phosphate phosphatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: (9S,10S)-10-hydroxy-9-(phosphonooxy)octadecanoate + H2O = (9S,10S)- 9,10-dihydroxyoctadecanoate + phosphate
+ H(2)O
= (9S,10S)- 9,10-dihydroxyoctadecanoate
+ phosphate
      Cofactor: Mg(2+)
   Enzyme class 3: E.C.  - Soluble epoxide hydrolase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: An epoxide + H2O = a glycol
+ H(2)O
= glycol
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   4 terms 
  Biological process     metabolic process   20 terms 
  Biochemical function     catalytic activity     11 terms  


DOI no: 10.1110/ps.051720206 Protein Sci 15:58-64 (2006)
PubMed id: 16322563  
Human soluble epoxide hydrolase: structural basis of inhibition by 4-(3-cyclohexylureido)-carboxylic acids.
G.A.Gomez, C.Morisseau, B.D.Hammock, D.W.Christianson.
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.
  Selected figure(s)  
Figure 3.
Figure 3. (A) Simulated annealing omit map of the human sEH-CU4 complex (contoured at 4.0 ). Hydrogen bonds are indicated by dotted lines. (B) Schematic representation of hydrogen bond interactions in the CU4 complex.
Figure 4.
Figure 4. (A) Simulated annealing omit map of the human sEH-CU6 complex (contoured at 4.0 ). Hydrogen bonds are indicated by dotted lines. (B) Schematic representation of hydrogen bond interactions in the CU6 complex.
  The above figures are reprinted by permission from the Protein Society: Protein Sci (2006, 15, 58-64) copyright 2006.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  20733953 S.Norwood, J.Liao, B.D.Hammock, and G.Y.Yang (2010).
Epoxyeicosatrienoic acids and soluble epoxide hydrolase: potential therapeutic targets for inflammation and its induced carcinogenesis.
  Am J Transl Res, 2, 447-457.  
20013303 Z.Zhang, Y.Sheng, K.Jiang, Z.Wang, Y.Zheng, and Q.Zhu (2010).
Bio-resolution of glycidyl (o, m, p)-methylphenyl ethers by Bacillus megaterium.
  Biotechnol Lett, 32, 513-516.  
19671760 J.Y.Liu, S.H.Park, C.Morisseau, S.H.Hwang, B.D.Hammock, and R.H.Weiss (2009).
Sorafenib has soluble epoxide hydrolase inhibitory activity, which contributes to its effect profile in vivo.
  Mol Cancer Ther, 8, 2193-2203.  
19218394 K.Jitsumori, R.Omi, T.Kurihara, A.Kurata, H.Mihara, I.Miyahara, K.Hirotsu, and N.Esaki (2009).
X-Ray crystallographic and mutational studies of fluoroacetate dehalogenase from Burkholderia sp. strain FA1.
  J Bacteriol, 191, 2630-2637.  
19856960 S.Lin, G.P.Horsman, Y.Chen, W.Li, and B.Shen (2009).
Characterization of the SgcF epoxide hydrolase supporting an (R)-vicinal diol intermediate for enediyne antitumor antibiotic C-1027 biosynthesis.
  J Am Chem Soc, 131, 16410-16417.  
19216074 T.Kasagami, I.H.Kim, H.J.Tsai, K.Nishi, B.D.Hammock, and C.Morisseau (2009).
Salicylate-urea-based soluble epoxide hydrolase inhibitors with high metabolic and chemical stabilities.
  Bioorg Med Chem Lett, 19, 1784-1789.  
18513744 B.Luo, C.Norris, E.S.Bolstad, D.A.Knecht, and D.F.Grant (2008).
Protein quaternary structure and expression levels contribute to peroxisomal-targeting-sequence-1-mediated peroxisomal import of human soluble epoxide hydrolase.
  J Mol Biol, 380, 31-41.  
17334823 K.H.Kim (2007).
Outliers in SAR and QSAR: is unusual binding mode a possible source of outliers?
  J Comput Aided Mol Des, 21, 63-86.  
17878749 N.Chiamvimonvat, C.M.Ho, H.J.Tsai, and B.D.Hammock (2007).
The soluble epoxide hydrolase as a pharmaceutical target for hypertension.
  J Cardiovasc Pharmacol, 50, 225-237.  
17616115 S.H.Hwang, H.J.Tsai, J.Y.Liu, C.Morisseau, and B.D.Hammock (2007).
Orally bioavailable potent soluble epoxide hydrolase inhibitors.
  J Med Chem, 50, 3825-3840.  
16908134 C.Morisseau, J.W.Newman, H.J.Tsai, P.A.Baecker, and B.D.Hammock (2006).
Peptidyl-urea based inhibitors of soluble epoxide hydrolases.
  Bioorg Med Chem Lett, 16, 5439-5444.  
16949285 S.H.Hwang, C.Morisseau, Z.Do, and B.D.Hammock (2006).
Solid-phase combinatorial approach for the optimization of soluble epoxide hydrolase inhibitors.
  Bioorg Med Chem Lett, 16, 5773-5777.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.