IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-37112-9.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-37112-9
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-37112-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Kaavya Krishna Kumar & Michael J. Robertson & Elina Thadhani & Haoqing Wang & Carl-Mikael Suomivuori & Alexander S. Powers & Lipin Ji & Spyros P. Nikas & Ron O. Dror & Asuka Inoue & Alexandros Makriya, 2023. "Structural basis for activation of CB1 by an endocannabinoid analog," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. Yuxia Qian & Jiening Wang & Linlin Yang & Yanru Liu & Lina Wang & Wei Liu & Yun Lin & Hong Yang & Lixin Ma & Sheng Ye & Shan Wu & Anna Qiao, 2022. "Activation and signaling mechanism revealed by GPR119-Gs complex structures," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    3. Yang Yang & Hye Jin Kang & Ruogu Gao & Jingjing Wang & Gye Won Han & Jeffrey F. DiBerto & Lijie Wu & Jiahui Tong & Lu Qu & Yiran Wu & Ryan Pileski & Xuemei Li & Xuejun Cai Zhang & Suwen Zhao & Terry K, 2023. "Structural insights into the human niacin receptor HCA2-Gi signalling complex," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    4. Kaihua Zhang & Hao Wu & Nicholas Hoppe & Aashish Manglik & Yifan Cheng, 2022. "Fusion protein strategies for cryo-EM study of G protein-coupled receptors," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    5. Hiroaki Akasaka & Tatsuki Tanaka & Fumiya K. Sano & Yuma Matsuzaki & Wataru Shihoya & Osamu Nureki, 2022. "Structure of the active Gi-coupled human lysophosphatidic acid receptor 1 complexed with a potent agonist," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    6. Yingying Nie & Zeming Qiu & Sijia Chen & Zhao Chen & Xiaocui Song & Yan Ma & Niu Huang & Jason G. Cyster & Sanduo Zheng, 2023. "Specific binding of GPR174 by endogenous lysophosphatidylserine leads to high constitutive Gs signaling," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    7. Na Wang & Xinheng He & Jing Zhao & Hualiang Jiang & Xi Cheng & Yu Xia & H. Eric Xu & Yuanzheng He, 2022. "Structural basis of leukotriene B4 receptor 1 activation," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    8. Xuan Zhang & Guibing Liu & Ya-Ni Zhong & Ru Zhang & Chuan-Cheng Yang & Canyang Niu & Xuanyu Pu & Jingjing Sun & Tianyao Zhang & Lejin Yang & Chao Zhang & Xiu Li & Xinyuan Shen & Peng Xiao & Jin-Peng S, 2024. "Structural basis of ligand recognition and activation of the histamine receptor family," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    9. Joshua A. Lees & João M. Dias & Francis Rajamohan & Jean-Philippe Fortin & Rebecca O’Connor & Jimmy X. Kong & Emily A. G. Hughes & Ethan L. Fisher & Jamison B. Tuttle & Gabrielle Lovett & Bethany L. K, 2023. "An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    10. Elizaveta Lyapina & Egor Marin & Anastasiia Gusach & Philipp Orekhov & Andrey Gerasimov & Aleksandra Luginina & Daniil Vakhrameev & Margarita Ergasheva & Margarita Kovaleva & Georgii Khusainov & Polin, 2022. "Structural basis for receptor selectivity and inverse agonism in S1P5 receptors," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    11. Karel Miettinen & Nattawat Leelahakorn & Aldo Almeida & Yong Zhao & Lukas R. Hansen & Iben E. Nikolajsen & Jens B. Andersen & Michael Givskov & Dan Staerk & Søren Bak & Sotirios C. Kampranis, 2022. "A GPCR-based yeast biosensor for biomedical, biotechnological, and point-of-use cannabinoid determination," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    12. Susanne Prokop & Péter Ábrányi-Balogh & Benjámin Barti & Márton Vámosi & Miklós Zöldi & László Barna & Gabriella M. Urbán & András Dávid Tóth & Barna Dudok & Attila Egyed & Hui Deng & Gian Marco Leggi, 2021. "PharmacoSTORM nanoscale pharmacology reveals cariprazine binding on Islands of Calleja granule cells," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    13. Xi Lin & Bo Chen & Yiran Wu & Yingqi Han & Ao Qi & Junyan Wang & Zhao Yang & Xiaohu Wei & Tingting Zhao & Lijie Wu & Xin Xie & Jinpeng Sun & Jie Zheng & Suwen Zhao & Fei Xu, 2023. "Cryo-EM structures of orphan GPR21 signaling complexes," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    14. Eunyoung Jeong & Yoojoong Kim & Jihong Jeong & Yunje Cho, 2021. "Structure of the class C orphan GPCR GPR158 in complex with RGS7-Gβ5," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    15. Jiale Liang & Asuka Inoue & Tatsuya Ikuta & Ruixue Xia & Na Wang & Kouki Kawakami & Zhenmei Xu & Yu Qian & Xinyan Zhu & Anqi Zhang & Changyou Guo & Zhiwei Huang & Yuanzheng He, 2023. "Structural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    16. Chulwon Choi & Jungnam Bae & Seonghan Kim & Seho Lee & Hyunook Kang & Jinuk Kim & Injin Bang & Kiheon Kim & Won-Ki Huh & Chaok Seok & Hahnbeom Park & Wonpil Im & Hee-Jung Choi, 2023. "Understanding the molecular mechanisms of odorant binding and activation of the human OR52 family," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37112-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.