Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-G(i) Complex Structures.
Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-G(i) Complex Structures.
复制标题
DOI：
10.1016/j.cell.2020.01.008
复制
发表时间：
2020-02-20
期刊：
影响因子：
64.5
通讯作者：
Liu ZJ
中科院分区：
文献类型：
--
作者：
Hua T;Li X;Wu L;Iliopoulos-Tsoutsouvas C;Wang Y;Wu M;Shen L;Brust CA;Nikas SP;Song F;Song X;Yuan S;Sun Q;Wu Y;Jiang S;Grim TW;Benchama O;Stahl EL;Zvonok N;Zhao S;Bohn LM;Makriyannis A;Liu ZJ
人类内源性大麻素系统主要通过激活大麻素受体CB1和CB2来调节多种生理过程。它们的高序列相似性、低激动剂选择性以及缺乏激活和G蛋白偶联知识阻碍了治疗应用的发展。重要的是，缺失的结构信息显著阻碍了有希望的CB2选择性激动剂药物的开发，这些药物用于治疗炎症和神经性疼痛，而没有CB1的精神活性。在这里，我们报告了合成大麻素结合的CB2和CB1与Gi复合的冷冻电子显微镜结构，以及激动剂结合的CB2晶体结构。重要的科学和治疗的好处，我们的研究结果揭示了不同的激活和信号传导机制，CB2选择性激动剂设计的结构基础，和胆固醇与CB1的意外相互作用，提示其内源性变构调节作用。大麻素受体CB2和CB1在其非活性、活性样和活化信号传导状态下的结构和模拟揭示了可能提供G蛋白选择性的残基差异、CB2激动剂在CB2和CB1中的独特结合行为以及胆固醇结合对CB1的调节的证据。
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 Gi, 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. Structure and simulations of cannabinoid receptors CB2 and CB1 in their inactive, active-like, and activated signaling states reveal residue differences that may provide G protein selectivity, the distinct binding behavior of CB2 agonists in CB2 and CB1, as well as evidence for modulation of CB1 by cholesterol binding.
登录
查看更多内容
影响因子：
7.3
作者：
Chen, X. P.;Yang, W.;Zhou, N. M.
通讯作者：
Zhou, N. M.
影响因子：
3
作者：
Bonomi, M.;Barducci, A.;Parrinello, M.
通讯作者：
Parrinello, M.
影响因子：
14.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Hua T;Vemuri K;Nikas SP;Laprairie RB;Wu Y;Qu L;Pu M;Korde A;Jiang S;Ho JH;Han GW;Ding K;Li X;Liu H;Hanson MA;Zhao S;Bohn LM;Makriyannis A;Stevens RC;Liu ZJ
通讯作者：
Liu ZJ
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH