1ZD3

Human soluble epoxide hydrolase 4-(3-cyclohexyluriedo)-butyric acid complex

1ZD3 の概要

• エントリーDOI: 10.2210/pdb1zd3/pdb
• 関連するPDBエントリー: 1S8O 1VJ5 1ZD2 1ZD4 1ZD5
• 分子名称: epoxide hydrolase 2, cytoplasmic, MAGNESIUM ION, PHOSPHATE ION, ... (6 entities in total)
• 機能のキーワード: domain-swapped dimer, hydrolase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P34913
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 64563.01

構造登録者

Gomez, G.A.,Morisseau, C.,Hammock, B.D.,Christianson, D.W. (登録日: 2005-04-14, 公開日: 2006-03-07, 最終更新日: 2023-08-23)

主引用文献

Gomez, G.A.,Morisseau, C.,Hammock, B.D.,Christianson, D.W.
Human soluble epoxide hydrolase: structural basis of inhibition by 4-(3-cyclohexylureido)-carboxylic acids
Protein Sci., 15:58-64, 2006

PubMed 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 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.

PubMed: 16322563
DOI: 10.1110/ps.051720206

実験手法

X-RAY DIFFRACTION (2.3 Å)