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Structural basis for activation of CB1 by an endocannabinoid analog

Author

Listed:
  • Kaavya Krishna Kumar

    (Stanford University School of Medicine)

  • Michael J. Robertson

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Elina Thadhani

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University
    Stanford University)

  • Haoqing Wang

    (Stanford University School of Medicine)

  • Carl-Mikael Suomivuori

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University
    Stanford University)

  • Alexander S. Powers

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University
    Stanford University)

  • Lipin Ji

    (Northeastern University)

  • Spyros P. Nikas

    (Northeastern University)

  • Ron O. Dror

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University
    Stanford University)

  • Asuka Inoue

    (Tohoku University)

  • Alexandros Makriyannis

    (Northeastern University
    Northeastern University)

  • Georgios Skiniotis

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University)

  • Brian Kobilka

    (Stanford University School of Medicine)

Abstract

Endocannabinoids (eCBs) are endogenous ligands of the cannabinoid receptor 1 (CB1), a G protein-coupled receptor that regulates a number of therapeutically relevant physiological responses. Hence, understanding the structural and functional consequences of eCB-CB1 interactions has important implications for designing effective drugs targeting this receptor. To characterize the molecular details of eCB interaction with CB1, we utilized AMG315, an analog of the eCB anandamide to determine the structure of the AMG315-bound CB1 signaling complex. Compared to previous structures, the ligand binding pocket shows some differences. Using docking, molecular dynamics simulations, and signaling assays we investigated the functional consequences of ligand interactions with the “toggle switch” residues F2003.36 and W3566.48. Further, we show that ligand-TM2 interactions drive changes to residues on the intracellular side of TM2 and are a determinant of efficacy in activating G protein. These intracellular TM2 rearrangements are unique to CB1 and are exploited by a CB1-specific allosteric modulator.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37864-4
    DOI: 10.1038/s41467-023-37864-4
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    References listed on IDEAS

    as
    1. G. Glenn Gregorio & Matthieu Masureel & Daniel Hilger & Daniel S. Terry & Manuel Juette & Hong Zhao & Zhou Zhou & Jose Manuel Perez-Aguilar & Maria Hauge & Signe Mathiasen & Jonathan A. Javitch & Hare, 2017. "Single-molecule analysis of ligand efficacy in β2AR–G-protein activation," Nature, Nature, vol. 547(7661), pages 68-73, July.
    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. 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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    1. Shun Kaneko & Shunsuke Imai & Tomomi Uchikubo-Kamo & Tamao Hisano & Nobuaki Asao & Mikako Shirouzu & Ichio Shimada, 2024. "Structural and dynamic insights into the activation of the μ-opioid receptor by an allosteric modulator," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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