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Structural basis of selective cannabinoid CB2 receptor activation

Author

Listed:
  • Xiaoting Li

    (iHuman Institute, ShanghaiTech University)

  • Hao Chang

    (iHuman Institute, ShanghaiTech University
    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
    ShanghaiTech University)

  • Yanan Yu

    (iHuman Institute, ShanghaiTech University
    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
    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
    ShanghaiTech University)

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.

Suggested Citation

  • 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 & Antoni, 2023. "Structural basis of selective cannabinoid CB2 receptor activation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37112-9
    DOI: 10.1038/s41467-023-37112-9
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    References listed on IDEAS

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