Crystal Structure of the Human Cannabinoid Receptor CB1

Tian Hua , Kiran Vemuri , Mengchen Pu , Lu Qu , Gye Won Han , Yiran Wu , Suwen Zhao , Wenqing Shui , Shanshan Li , Anisha Korde , Robert B. Laprairie , Edward L. Stahl , Jo-Hao Ho , Nikolai Zvonok , Han Zhou , Irina Kufareva , Beili Wu , Qiang Zhao , Michael A. Hanson , Laura M. Bohn, Alexandros Makriyannis, Raymond C. Stevens and Zhi-Jie Liu

(2016) Cell, Volume 167, Issue 3, p750–762.e14, 20

Link to abstract

Cannabinoid receptor 1 (CB₁) is the principal target of Δ⁹-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB₁ is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. Here, we present the 2.8 Å crystal structure of human CB₁ in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study. The structure of the CB₁-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding. In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB₁ ligands, such as THC, and synthetic cannabinoids. This enhances our understanding of the molecular basis for the physiological functions of CB₁ and provides new opportunities for the design of next-generation CB₁-targeting pharmaceuticals.