5W58

Crystal Complex of Cyclooxygenase-2: (S)-ARN-2508 (a dual COX and FAAH inhibitor)

5W58 の概要

• エントリーDOI: 10.2210/pdb5w58/pdb
• 関連するBIRD辞書のPRD_ID: PRD_900017
• 分子名称: Prostaglandin G/H synthase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• 機能のキーワード: cyclooxygenase, protein-inhibitor complex, prostaglandin, faah-cox dual inhibition, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 69991.39

構造登録者

Xu, S.,Goodman, M.C.,Banerjee, S.,Piomelli, D.,Marnett, L.J. (登録日: 2017-06-14, 公開日: 2018-01-31, 最終更新日: 2024-11-06)

主引用文献

Goodman, M.C.,Xu, S.,Rouzer, C.A.,Banerjee, S.,Ghebreselasie, K.,Migliore, M.,Piomelli, D.,Marnett, L.J.
Dual cyclooxygenase-fatty acid amide hydrolase inhibitor exploits novel binding interactions in the cyclooxygenase active site.
J. Biol. Chem., 293:3028-3038, 2018

PubMed Abstract: The cyclooxygenases COX-1 and COX-2 oxygenate arachidonic acid (AA) to prostaglandin H (PGH). COX-2 also oxygenates the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA) to the corresponding PGH analogs. Both enzymes are targets of nonsteroidal anti-inflammatory drugs (NSAIDs), but NSAID-mediated COX inhibition is associated with gastrointestinal toxicity. One potential strategy to counter this toxicity is to also inhibit fatty acid amide hydrolase (FAAH), which hydrolyzes bioactive fatty acid ethanolamides (FAEs) into fatty acids and ethanolamine. Here, we investigated the mechanism of COX inhibition by ARN2508, an NSAID that inhibits both COXs and FAAH with high potency, target selectivity, and decreased gastrointestinal toxicity in mouse models, presumably due to its ability to increase levels of FAEs. A 2.27-Å-resolution X-ray crystal structure of the COX-2·()-ARN2508 complex reveals that ARN2508 adopts a binding pose similar to that of its parent NSAID flurbiprofen. However, ARN2508's alkyl tail is inserted deep into the top channel, an active site region not exploited by any previously reported NSAID. As for flurbiprofen, ARN2508's potency is highly dependent on the configuration of the α-methyl group. Thus, ()-ARN2508 is more potent than ()-ARN2508 for inhibition of AA oxygenation by both COXs and 2-AG oxygenation by COX-2. Also, similarly to ()-flurbiprofen, ()-ARN2508 exhibits substrate selectivity for inhibition of 2-AG oxygenation. Site-directed mutagenesis confirms the importance of insertion of the alkyl tail into the top channel for ()-ARN2508's potency and suggests a role for Ser-530 as a determinant of the inhibitor's slow rate of inhibition compared with that of ()-flurbiprofen.

PubMed: 29326169
DOI: 10.1074/jbc.M117.802058

実験手法

X-RAY DIFFRACTION (2.267 Å)