The cannabinoid receptor 1 (CB1) is the principal target of the psychoactive constituent of marijuana, the partial agonist Δ9-tetrahydrocannabinol (Δ9-THC)1. Here we report two agonist-bound crystal structures of human CB1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 Å and 2.95 Å resolution, respectively. The two CB1–agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state2, including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G-protein-binding region. In addition, a ‘twin toggle switch’ of Phe2003.36 and Trp3566.48 (superscripts denote Ballesteros–Weinstein numbering3) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB1 and provide a molecular basis for predicting the binding modes of Δ9-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB1 seems to be a common feature among certain class A G-protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.

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This work was supported by the NSF of China grant 31330019 (Z.-J.L.), the MOST of China grants 2014CB910400 (Z.-J.L.) and 2015CB910104 (Z.-J.L.), NSF of Shanghai 16ZR1448500 grant (S.Z.), Key R&D Program of China grant 2016YCF0905902 (S.Z.), NIH grants R01DA041435 (R.C.S., A.M.), P01DA009158 (A.M., L.M.B.), R37DA023142 (A.M.), NSF grants, Shanghai Municipal Government, ShanghaiTech University and GPCR Consortium. The diffraction data were collected at GM/CA@APS of Argonne National Laboratory, X06SA@SLS of the Paul Scherrer Insitute, and BL41XU@Spring-8 with JASRI proposals 2015B1031 and 2016A2731. We thank M. Wang, C.-Y. Huang, V. Olieric, M. Audet and M.-Y. Lee for their help with data collection, A. Walker for critical review of the manuscript, and F. Sun for high-resolution mass spectrometry analysis.

Author information

Author notes

    • Kiran Vemuri
    •  & Spyros P. Nikas

    These authors contributed equally to this work.


  1. iHuman Institute, ShanghaiTech University, Shanghai 201210, China

    • Tian Hua
    • , Yiran Wu
    • , Lu Qu
    • , Mengchen Pu
    • , Kang Ding
    • , Suwen Zhao
    • , Raymond C. Stevens
    •  & Zhi-Jie Liu
  2. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China

    • Tian Hua
    • , Lu Qu
    •  & Zhi-Jie Liu
  3. University of Chinese Academy of Sciences, Beijing 100049, China

    • Tian Hua
    • , Lu Qu
    •  & Kang Ding
  4. Center for Drug Discovery, Department of Pharmaceutical Sciences; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, USA

    • Kiran Vemuri
    • , Spyros P. Nikas
    • , Anisha Korde
    • , Shan Jiang
    •  & Alexandros Makriyannis
  5. Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute, Jupiter, Florida 33458, USA

    • Robert B. Laprairie
    • , Jo-Hao Ho
    •  & Laura M. Bohn
  6. Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA

    • Gye Won Han
    •  & Raymond C. Stevens
  7. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China

    • Kang Ding
    • , Suwen Zhao
    • , Raymond C. Stevens
    •  & Zhi-Jie Liu
  8. Complex Systems Division, Beijing Computational Science Research Center, Beijing 100193, China

    • Xuanxuan Li
    •  & Haiguang Liu
  9. GPCR Consortium, San Marcos, California 92078, USA

    • Michael A. Hanson


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T.H.: crystallization, data collection, structure determination and analysis; K.V., S.P.N., S.J.: design, synthesis and characterization of ligands; Y.W.: docking, molecular dynamics simulation; L.Q., M.P.: data collection and processing, structure refinement; G.W.H., M.A.H.: structure refinement and data analysis. R.B.L. and J.-H.H.: functional studies, mutations; A.K.: radioligand binding assays; K.D.: structure analysis; X.L. and H.L.: molecular dynamics simulations; S.Z.: supervision of structure and simulation analysis; L.M.B.: design and supervision of functional and kinetic studies; A.M.: supervision on agonist conceptual design, synthesis and characterization; R.C.S.: project conception, data analysis supervision; Z.J.L.: design and supervision of experiments, data analysis; Z.J.L., T.H., R.C.S., A.M., L.M.B. and S.Z. wrote the manuscript with discussions and improvements from M.A.H., K.V., S.P.N. and Y.W.

Competing interests

A.M. is a founder of MAKScientific, LLC. R.C.S. is a board member and shareholder with Birdrock Bio. The remaining authors declare no competing financial interests.

Corresponding authors

Correspondence to Suwen Zhao or Laura M. Bohn or Alexandros Makriyannis or Zhi-Jie Liu.

Reviewer Information Nature thanks G. Kunos and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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