3K83

Crystal Structure Analysis of a Biphenyl/Oxazole/Carboxypyridine alpha-ketoheterocycle Inhibitor Bound to a Humanized Variant of Fatty Acid Amide Hydrolase

3K83 の概要

• エントリーDOI: 10.2210/pdb3k83/pdb
• 関連するPDBエントリー: 2wj1 2wj2 3K84 3k7f
• 分子名称: Fatty-acid amide hydrolase 1, 6-[2-(3-biphenyl-4-ylpropanoyl)-1,3-oxazol-5-yl]pyridine-2-carboxylic acid, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: faah, oxazole, conjugate, covalent modification, hydrolase, membrane, transmembrane, monotopic, fatty acid, serine hydrolase, endocannabinoid, reversible inhibitor.
• 由来する生物種: Rattus norvegicus (rat)
• 細胞内の位置: Endoplasmic reticulum membrane; Single-pass membrane protein: P97612
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 127241.94

構造登録者

Mileni, M.,Stevens, R.C.,Boger, D.L. (登録日: 2009-10-13, 公開日: 2009-12-01, 最終更新日: 2024-11-06)

主引用文献

Mileni, M.,Garfunkle, J.,Ezzili, C.,Kimball, F.S.,Cravatt, B.F.,Stevens, R.C.,Boger, D.L.
X-ray crystallographic analysis of alpha-ketoheterocycle inhibitors bound to a humanized variant of fatty acid amide hydrolase.
J.Med.Chem., 53:230-240, 2010

PubMed Abstract: Three cocrystal X-ray structures of the alpha-ketoheterocycle inhibitors 3-5 bound to a humanized variant of fatty acid amide hydrolase (FAAH) are disclosed and comparatively discussed alongside those of 1 (OL-135) and its isomer 2. These five X-ray structures systematically probe each of the three active site regions key to substrate or inhibitor binding: (1) the conformationally mobile acyl chain-binding pocket and membrane access channel responsible for fatty acid amide substrate and inhibitor acyl chain binding, (2) the atypical active site catalytic residues and surrounding oxyanion hole that covalently binds the core of the alpha-ketoheterocycle inhibitors captured as deprotonated hemiketals mimicking the tetrahedral intermediate of the enzyme-catalyzed reaction, and (3) the cytosolic port and its uniquely important imbedded ordered water molecules and a newly identified anion binding site. The detailed analysis of their key active site interactions and their implications on the interpretation of the available structure-activity relationships are discussed providing important insights for future design.

PubMed: 19924997
DOI: 10.1021/jm9012196

実験手法

X-RAY DIFFRACTION (2.251 Å)