6V3R

Crystal structure of murine cycloxygenase in complex with a harmaline analog, 4,9-dihydro-3H-pyrido[3,4-b]indole

6V3R の概要

• エントリーDOI: 10.2210/pdb6v3r/pdb
• 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, PROTOPORPHYRIN IX CONTAINING FE, ... (7 entities in total)
• 機能のキーワード: prostaglandin g/h synthase 2, cyclooxygenase-2, oxidoreductase, inhibitor complex, membrane protein, 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: 4
• 化学式量合計: 277204.12

構造登録者

Xu, S.,Uddin, M.J.,Banerjee, S.,Marnett, L.J. (登録日: 2019-11-26, 公開日: 2020-02-26, 最終更新日: 2024-11-13)

主引用文献

Uddin, M.J.,Xu, S.,Crews, B.C.,Aleem, A.M.,Ghebreselasie, K.,Banerjee, S.,Marnett, L.J.
Harmaline Analogs as Substrate-Selective Cyclooxygenase-2 Inhibitors.
Acs Med.Chem.Lett., 11:1881-1885, 2020

PubMed Abstract: We report the design, synthesis, and evaluation of a series of harmaline analogs as selective inhibitors of 2-arachidonylglycerol (2-AG) oxygenation over arachidonic acid (AA) oxygenation by purified cyclooxygenase-2 (COX-2). A fused tricyclic harmaline analog containing a CHO substituent at C-6 and a CH group at the C-1 position of 4,9-dihydro-3-pyrido[3,4-]indole (compound ) was the best substrate-selective COX-2 inhibitor of those evaluated, exhibiting a 2AG-selective COX-2 inhibitory IC of 0.022 μM as compared to >1 μM for AA. The 2.66 Å resolution crystal complex of COX-2 with compound revealed that this series of tricyclic indoles binds in the cyclooxygenase channel by flipping the side chain of L531 toward the dimer interface. This novel tricyclic indole series provides the foundation for the development of promising substrate-selective molecules capable of increasing endocannabinoid (EC) levels in the brain to offer new treatments for a variety of diseases, from pain and inflammation to stress and anxiety disorders.

PubMed: 33062168
DOI: 10.1021/acsmedchemlett.9b00555

実験手法

X-RAY DIFFRACTION (2.66 Å)