2WAP

3D-crystal structure of humanized-rat fatty acid amide hydrolase (FAAH) conjugated with the drug-like urea inhibitor PF-3845

2WAP の概要

• エントリーDOI: 10.2210/pdb2wap/pdb
• 関連するPDBエントリー: 1MT5 2VYA
• 分子名称: FATTY-ACID AMIDE HYDROLASE 1, 4-(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}benzyl)piperidine-1-carboxylic acid, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: fatty acid amide hydrolase, urea inhibitor, golgi apparatus, endoplasmic reticulum, acyl- enzyme, transmembrane, phosphoprotein, faah, drug, membrane, hydrolase, 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: 120519.18

構造登録者

Mileni, M.,Kamtekar, S.,Stevens, R.C. (登録日: 2009-02-11, 公開日: 2009-05-05, 最終更新日: 2024-11-20)

主引用文献

Ahn, K.,Johnson, D.S.,Mileni, M.,Beidler, D.,Long, J.Z.,Mckinney, M.K.,Weerapana, E.,Sadagopan, N.,Liimatta, M.,Smith, S.E.,Lazerwith, S.,Stiff, C.,Kamtekar, S.,Bhattacharya, K.,Zhang, Y.,Swaney, S.,Vanbecelaere, K.,Stevens, R.C.,Cravatt, B.F.
Discovery and Characterization of a Highly Selective Faah Inhibitor that Reduces Inflammatory Pain.
Chem.Biol., 16:411-, 2009

PubMed Abstract: Endocannabinoids are lipid signaling molecules that regulate a wide range of mammalian behaviors, including pain, inflammation, and cognitive/emotional state. The endocannabinoid anandamide is principally degraded by the integral membrane enzyme fatty acid amide hydrolase (FAAH), and there is currently much interest in developing FAAH inhibitors to augment endocannabinoid signaling in vivo. Here, we report the discovery and detailed characterization of a highly efficacious and selective FAAH inhibitor, PF-3845. Mechanistic and structural studies confirm that PF-3845 is a covalent inhibitor that carbamylates FAAH's serine nucleophile. PF-3845 selectively inhibits FAAH in vivo, as determined by activity-based protein profiling; raises brain anandamide levels for up to 24 hr; and produces significant cannabinoid receptor-dependent reductions in inflammatory pain. These data thus designate PF-3845 as a valuable pharmacological tool for in vivo characterization of the endocannabinoid system.

PubMed: 19389627
DOI: 10.1016/J.CHEMBIOL.2009.02.013

実験手法

X-RAY DIFFRACTION (2.8 Å)