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人大麻素受体CB2-Gi信号复合物冷冻电镜结构获解析
作者:小柯机器人 发布时间:2020/2/12 17:06:38

近日,美国匹兹堡大学Xiang-Qun Xie、Cheng Zhang和中国科学院上海药物所徐华强等研究人合作解析了人类大麻素受体CB2-Gi信号复合物的冷冻电镜结构。这一研究成果于2020年1月30日在线发表在国际学术期刊《细胞》上。

研究人员报告了结合激动剂WIN 55,212-2的人类CB2-Gi信号复合物的冷冻电镜结构。3D结构揭示了WIN 55,212-2的结合模式以及将CB2激动剂与拮抗剂区分开的结构决定簇。进一步结构分析与计算对接结果揭示了CB2和CB1之间在受体激活、配体识别和Gi耦合方面的差异。这些发现有望促进靶向大麻素系统药物的发现。
 
据悉,选择性靶向CB2的药物有望治疗神经退行性疾病、炎症和疼痛,同时避免CB1介导的精神副作用。对CB2激活和信号转导的机制了解甚少,但这对药物设计至关重要。
 
附:英文原文

Title: Cryo-EM Structure of the Human Cannabinoid Receptor CB2-Gi Signaling Complex

Author: Changrui Xing, Youwen Zhuang, Ting-Hai Xu, Zhiwei Feng, X. Edward Zhou, Maozi Chen, Lei Wang, Xing Meng, Ying Xue, Junmei Wang, Heng Liu, Terence Francis McGuire, Gongpu Zhao, Karsten Melcher, Cheng Zhang, H. Eric Xu, Xiang-Qun Xie

Issue&Volume: January 30, 2020

Abstract: Drugs selectively targeting CB2 hold promise for treating neurodegenerative disorders,inflammation, and pain while avoiding psychotropic side effects mediated by CB1. Themechanisms underlying CB2 activation and signaling are poorly understood but criticalfor drug design. Here we report the cryo-EM structure of the human CB2-Gi signaling complex bound to the agonist WIN 55,212-2. The 3D structure reveals thebinding mode of WIN 55,212-2 and structural determinants for distinguishing CB2 agonistsfrom antagonists, which are supported by a pair of rationally designed agonist andantagonist. Further structural analyses with computational docking results uncoverthe differences between CB2 and CB1 in receptor activation, ligand recognition, andGi coupling. These findings are expected to facilitate rational structure-based discoveryof drugs targeting the cannabinoid system.

DOI: 10.1016/j.cell.2020.01.007

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30054-4

期刊信息
Cell:《细胞》,创刊于1974年。隶属于细胞出版社,最新IF:36.216
官方网址:https://www.cell.com/