Structural basis of selective cannabinoid CB2 receptor activation

Xiaoting Li, Hao Chang, Jara Bouma, Laura V. Paus, Partha Mukhopadhyay, Janos Paloczi, Mohammed Mustafa, Cas Horst, Sanjay Sunil Kumar, Lijie Wu, Yanan Yu, Richard J. B. H. N. Berg, Antonius P. A. Janssen, Aron Lichtman, Zhi-Jie Liu (), Pal Pacher (), Mario Stelt (), Laura H. Heitman () and Tian Hua ()
Additional contact information
Xiaoting Li: iHuman Institute, ShanghaiTech University
Hao Chang: iHuman Institute, ShanghaiTech University
Jara Bouma: Leiden University, Oncode Institute
Laura V. Paus: Leiden University, Oncode Institute
Partha Mukhopadhyay: National Institute of Health/National Institute on Alcohol Abuse and Alcoholism
Janos Paloczi: National Institute of Health/National Institute on Alcohol Abuse and Alcoholism
Mohammed Mustafa: Virginia Commonwealth University
Cas Horst: Leiden University, Oncode Institute
Sanjay Sunil Kumar: Leiden University, Oncode Institute
Lijie Wu: iHuman Institute, ShanghaiTech University
Yanan Yu: iHuman Institute, ShanghaiTech University
Richard J. B. H. N. Berg: Leiden University, Oncode Institute
Antonius P. A. Janssen: Leiden University, Oncode Institute
Aron Lichtman: Virginia Commonwealth University
Zhi-Jie Liu: iHuman Institute, ShanghaiTech University
Pal Pacher: National Institute of Health/National Institute on Alcohol Abuse and Alcoholism
Mario Stelt: Leiden University, Oncode Institute
Laura H. Heitman: Leiden University, Oncode Institute
Tian Hua: iHuman Institute, ShanghaiTech University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Cannabinoid CB2 receptor (CB2R) agonists are investigated as therapeutic agents in the clinic. However, their molecular mode-of-action is not fully understood. Here, we report the discovery of LEI-102, a CB2R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate the selective CB2R activation by binding kinetics, site-directed mutagenesis, and cryo-EM studies. We identify key residues for CB2R activation. Highly lipophilic HU308 and the endocannabinoids, but not the more polar LEI-102, APD371, and CP55,940, reach the binding pocket through a membrane channel in TM1-TM7. Favorable physico-chemical properties of LEI-102 enable oral efficacy in a chemotherapy-induced nephropathy model. This study delineates the molecular mechanism of CB2R activation by selective agonists and highlights the role of lipophilicity in CB2R engagement. This may have implications for GPCR drug design and sheds light on their activation by endogenous ligands.

Date: 2023
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DOI: 10.1038/s41467-023-37112-9

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