Structural basis of selective cannabinoid CB2 receptor activation
Nature Communications, vol. 14, pp. 1447
Abstract
Abstract Cannabinoid CB 2 receptor (CB 2 R) 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 CB 2 R agonist, used in conjunction with three other CBR ligands (APD371, HU308, and CP55,940) to investigate the selective CB 2 R activation by binding kinetics, site-directed mutagenesis, and cryo-EM studies. We identify key residues for CB 2 R 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 CB 2 R activation by selective agonists and highlights the role of lipophilicity in CB 2 R engagement. This may have implications for GPCR drug design and sheds light on their activation by endogenous ligands.
Authors 19
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Affiliation as printed
iHuman Institute, ShanghaiTech University, Shanghai, 201210, China
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Affiliation as printed
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
iHuman Institute, ShanghaiTech University, Shanghai, 201210, China
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Jara Bouma Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research Oncode Institute
Affiliation as printed
Division of Drug Discovery and Safety, Leiden Academic Center for Drug Research, Leiden University, Oncode Institute, Leiden, the Netherlands
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Leiden University · Oncode Institute
Affiliation as printed
Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Oncode Institute, Leiden, the Netherlands
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National Institutes of Health · National Institute on Alcohol Abuse and Alcoholism
Affiliation as printed
Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute of Health/National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA
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National Institutes of Health · National Institute on Alcohol Abuse and Alcoholism
Affiliation as printed
Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute of Health/National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA
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Virginia Commonwealth University
Affiliation as printed
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA
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Cas van der Horst corresponding Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research Oncode Institute
Affiliation as printed
Division of Drug Discovery and Safety, Leiden Academic Center for Drug Research, Leiden University, Oncode Institute, Leiden, the Netherlands
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Sanjay Sunil Kumar Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research Oncode Institute
Affiliation as printed
Division of Drug Discovery and Safety, Leiden Academic Center for Drug Research, Leiden University, Oncode Institute, Leiden, the Netherlands
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Affiliation as printed
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
iHuman Institute, ShanghaiTech University, Shanghai, 201210, China
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Affiliation as printed
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
iHuman Institute, ShanghaiTech University, Shanghai, 201210, China
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Leiden University · Oncode Institute
Affiliation as printed
Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Oncode Institute, Leiden, the Netherlands
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Leiden University · Oncode Institute
Affiliation as printed
Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Oncode Institute, Leiden, the Netherlands
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Virginia Commonwealth University
Affiliation as printed
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA
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Zhi‐Jie Liu corresponding
Affiliation as printed
School of Life Science and Technology, ShanghaiTech University, Shanghai, China. liuzhj@shanghaitech.edu.cn
iHuman Institute, ShanghaiTech University, Shanghai, 201210, China. liuzhj@shanghaitech.edu.cn
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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Pál Pacher corresponding
National Institutes of Health · National Institute on Alcohol Abuse and Alcoholism
Affiliation as printed
Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute of Health/National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA. pacher@mail.nih.gov
Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute of Health/National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA
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Leiden University · Oncode Institute
Affiliation as printed
Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Oncode Institute, Leiden, the Netherlands. m.van.der.stelt@chem.leidenuniv.nl
Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Oncode Institute, Leiden, the Netherlands
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Laura H. Heitman corresponding Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research Oncode Institute
Affiliation as printed
Division of Drug Discovery and Safety, Leiden Academic Center for Drug Research, Leiden University, Oncode Institute, Leiden, the Netherlands. l.h.heitman@lacdr.leidenuniv.nl
Division of Drug Discovery and Safety, Leiden Academic Center for Drug Research, Leiden University, Oncode Institute, Leiden, the Netherlands
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Tian Hua corresponding
Affiliation as printed
School of Life Science and Technology, ShanghaiTech University, Shanghai, China. huatian@shanghaitech.edu.cn
iHuman Institute, ShanghaiTech University, Shanghai, 201210, China. huatian@shanghaitech.edu.cn
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
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