1EK1

CRYSTAL STRUCTURE OF MURINE SOLUBLE EPOXIDE HYDROLASE COMPLEXED WITH CIU INHIBITOR

Summary for 1EK1

• Entry DOI: 10.2210/pdb1ek1/pdb
• Related: 1CQZ 1CR6 1EK2
• Descriptor: EPOXIDE HYDROLASE, N-CYCLOHEXYL-N'-(4-IODOPHENYL)UREA (3 entities in total)
• Functional Keywords: homodimer, alpha/beta hydrolase fold, disubstituted urea inhibitor, hydrolase
• Biological source: Mus musculus (house mouse)
• Cellular location: Cytoplasm: P34914
• Total number of polymer chains: 2
• Total formula weight: 125852.46

Authors

Argiriadi, M.A.,Morisseau, C.,Goodrow, M.H.,Dowdy, D.L.,Hammock, B.D.,Christianson, D.W. (deposition date: 2000-03-06, release date: 2000-05-31, Last modification date: 2024-02-07)

Primary citation

Argiriadi, M.A.,Morisseau, C.,Goodrow, M.H.,Dowdy, D.L.,Hammock, B.D.,Christianson, D.W.
Binding of alkylurea inhibitors to epoxide hydrolase implicates active site tyrosines in substrate activation.
J.Biol.Chem., 275:15265-15270, 2000

PubMed Abstract: The structures of two alkylurea inhibitors complexed with murine soluble epoxide hydrolase have been determined by x-ray crystallographic methods. The alkyl substituents of each inhibitor make extensive hydrophobic contacts in the soluble epoxide hydrolase active site, and each urea carbonyl oxygen accepts hydrogen bonds from the phenolic hydroxyl groups of Tyr(381) and Tyr(465). These hydrogen bond interactions suggest that Tyr(381) and/or Tyr(465) are general acid catalysts that facilitate epoxide ring opening in the first step of the hydrolysis reaction; Tyr(465) is highly conserved among all epoxide hydrolases, and Tyr(381) is conserved among the soluble epoxide hydrolases. In one enzyme-inhibitor complex, the urea carbonyl oxygen additionally interacts with Gln(382). If a comparable interaction occurs in catalysis, then Gln(382) may provide electrostatic stabilization of partial negative charge on the epoxide oxygen. The carboxylate side chain of Asp(333) accepts a hydrogen bond from one of the urea NH groups in each enzyme-inhibitor complex. Because Asp(333) is the catalytic nucleophile, its interaction with the partial positive charge on the urea NH group mimics its approach toward the partial positive charge on the electrophilic carbon of an epoxide substrate. Accordingly, alkylurea inhibitors mimic features encountered in the reaction coordinate of epoxide ring opening, and a structure-based mechanism is proposed for leukotoxin epoxide hydrolysis.

PubMed: 10747889
DOI: 10.1074/jbc.M000278200

Experimental method

X-RAY DIFFRACTION (3.1 Å)