Crystal structures of agonist-bound human cannabinoid receptor CB1

Tian Hua, Kiran Vemuri, Spyros P. Nikas, Yiran Wu, Lu Qu, Mengchen Pu, Anisha Korde, Shan Jiang, Jo-Hao Ho, Gye Won Han, Kang Ding, Xuanxuan Li, Haiguang Liu, Michael A. Hanson, Suwen Zhao (), Laura M. Bohn (), Alexandros Makriyannis (), Raymond C. Stevens and Zhi-Jie Liu ()
Additional contact information
Tian Hua: ShanghaiTech University
Kiran Vemuri: Northeastern University
Spyros P. Nikas: Northeastern University
Yiran Wu: ShanghaiTech University
Lu Qu: ShanghaiTech University
Mengchen Pu: ShanghaiTech University
Anisha Korde: Northeastern University
Shan Jiang: Northeastern University
Jo-Hao Ho: The Scripps Research Institute
Gye Won Han: University of Southern California
Kang Ding: ShanghaiTech University
Xuanxuan Li: Beijing Computational Science Research Center
Haiguang Liu: Beijing Computational Science Research Center
Michael A. Hanson: GPCR Consortium
Suwen Zhao: ShanghaiTech University
Laura M. Bohn: The Scripps Research Institute
Alexandros Makriyannis: Northeastern University
Raymond C. Stevens: ShanghaiTech University
Zhi-Jie Liu: ShanghaiTech University

Nature, 2025, vol. 646, issue 8085, 754-758

Abstract: Abstract Cannabinoid receptor 1 (CB1) is the primary target of the partial agonist Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive constituent of marijuana1. Here we report two agonist-bound crystal structures of human CB1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841). The two CB1–agonist complexes reveal important conformational changes in the overall structure relative to the antagonist-bound state2, including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G protein-binding region. Furthermore, a twin toggle switch of Phe2003.36 and Trp3566.48 (where the superscripts denote Ballesteros–Weinstein numbering3) is experimentally observed and seems to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB1 and provide a molecular basis for predicting the binding modes of Δ9-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB1 seems to be a common feature among certain class A G protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.

Date: 2025
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DOI: 10.1038/s41586-025-09454-5

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