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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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    1. Xi Lin & Mingyue Li & Niandong Wang & Yiran Wu & Zhipu Luo & Shimeng Guo & Gye-Won Han & Shaobai Li & Yang Yue & Xiaohu Wei & Xin Xie & Yong Chen & Suwen Zhao & Jian Wu & Ming Lei & Fei Xu, 2020. "Structural basis of ligand recognition and self-activation of orphan GPR52," Nature, Nature, vol. 579(7797), pages 152-157, March.
    2. Tian Hua & Kiran Vemuri & Spyros P. Nikas & Robert B. Laprairie & Yiran Wu & Lu Qu & Mengchen Pu & Anisha Korde & Shan Jiang & Jo-Hao Ho & Gye Won Han & Kang Ding & Xuanxuan Li & Haiguang Liu & Michae, 2017. "Crystal structures of agonist-bound human cannabinoid receptor CB1," Nature, Nature, vol. 547(7664), pages 468-471, July.
    3. Marjolein Soethoudt & Uwe Grether & Jürgen Fingerle & Travis W. Grim & Filomena Fezza & Luciano de Petrocellis & Christoph Ullmer & Benno Rothenhäusler & Camille Perret & Noortje van Gils & David Finl, 2017. "Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    4. Zhenhua Shao & Jie Yin & Karen Chapman & Magdalena Grzemska & Lindsay Clark & Junmei Wang & Daniel M. Rosenbaum, 2016. "High-resolution crystal structure of the human CB1 cannabinoid receptor," Nature, Nature, vol. 540(7634), pages 602-606, December.
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