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キーワード
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

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Structure paper

タイトル	Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-G Complex Structures.
ジャーナル・号・ページ	Cell, Vol. 180, Issue 4, Page 655-665.e18, Year 2020
掲載日	2020年2月20日
著者	Tian Hua / Xiaoting Li / Lijie Wu / Christos Iliopoulos-Tsoutsouvas / Yuxia Wang / Meng Wu / Ling Shen / Christina A Brust / Spyros P Nikas / Feng Song / Xiyong Song / Shuguang Yuan / Qianqian Sun / Yiran Wu / Shan Jiang / Travis W Grim / Othman Benchama / Edward L Stahl / Nikolai Zvonok / Suwen Zhao / Laura M Bohn / Alexandros Makriyannis / Zhi-Jie Liu /
PubMed 要旨	Human endocannabinoid systems modulate multiple physiological processes mainly through the activation of cannabinoid receptors CB1 and CB2. Their high sequence similarity, low agonist selectivity, ...Human endocannabinoid systems modulate multiple physiological processes mainly through the activation of cannabinoid receptors CB1 and CB2. Their high sequence similarity, low agonist selectivity, and lack of activation and G protein-coupling knowledge have hindered the development of therapeutic applications. Importantly, missing structural information has significantly held back the development of promising CB2-selective agonist drugs for treating inflammatory and neuropathic pain without the psychoactivity of CB1. Here, we report the cryoelectron microscopy structures of synthetic cannabinoid-bound CB2 and CB1 in complex with G, as well as agonist-bound CB2 crystal structure. Of important scientific and therapeutic benefit, our results reveal a diverse activation and signaling mechanism, the structural basis of CB2-selective agonists design, and the unexpected interaction of cholesterol with CB1, suggestive of its endogenous allosteric modulating role.
リンク	Cell / PubMed:32004463 / PubMed Central
手法	EM (単粒子) / X線回折
解像度	2.9 - 3.2 Å
構造データ	0744 6kpf EMDB-0744, PDB-6kpf: Cryo-EM structure of a class A GPCR with G protein complex 手法: EM (単粒子) / 解像度: 2.9 Å 0745 6kpg EMDB-0745, PDB-6kpg: Cryo-EM structure of CB1-G protein complex 手法: EM (単粒子) / 解像度: 3.0 Å PDB-6kpc: Crystal structure of an agonist bound GPCR 手法: X-RAY DIFFRACTION / 解像度: 3.2 Å
化合物	ChemComp-E3R: 7-[(6aR,9R,10aR)-1-Hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl]- 7-methyloctanenitrile ChemComp-8D0: (6~{a}~{R},9~{R},10~{a}~{R})-9-(hydroxymethyl)-3-(8-isothiocyanato-2-methyl-octan-2-yl)-6,6-dimethyl-6~{a},7,8,9,10,10~{a}-hexahydrobenzo[c]chromen-1-ol / AM-841
由来	homo sapiens (ヒト) enterobacteria phage rb59 (ファージ)
キーワード	MEMBRANE PROTEIN (膜タンパク質) / GPCR (Gタンパク質共役受容体) / LCP / agonist (アゴニスト) / Gi Protein (Giタンパク質αサブユニット) / G protein (Gタンパク質) / cryo-EM (低温電子顕微鏡法)