G蛋白偶联的人类大麻素受体1(CB1)是疼痛管理的一个有前途的治疗目标,炎症,肥胖,和药物滥用障碍。迄今为止,合成的激动剂结合形式的CB1-Gi复合物的结构已经被解析。然而,CB1的商业药物识别和Gq偶联机制仍然难以捉摸。在这里,CB1-Gq复合物的低温电子显微镜(cryo-EM)结构,非诺贝特结合形式,在近原子分辨率下,据报道。该结构阐明了CB1精确识别非诺贝特和Gq蛋白偶联的微妙机制,并将促进未来的药物发现和设计。
The G-protein-coupled human cannabinoid receptor 1 (CB1) is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. The structures of CB1-Gi complexes in synthetic agonist-bound forms have been resolved to date. However, the commercial drug recognition and Gq coupling mechanisms of CB1 remain elusive. Herein, the cryo-electron microscopy (cryo-EM) structure of CB1-Gq complex, in fenofibrate-bound form, at near-atomic resolution, is reported. The structure elucidates the delicate mechanisms of the precise fenofibrate recognition and Gq protein coupling by CB1 and will facilitate future drug discovery and design.