Letter | Published:

High-resolution crystal structure of the human CB1 cannabinoid receptor

Nature volume 540, pages 602606 (22 December 2016) | Download Citation

Abstract

The human cannabinoid G-protein-coupled receptors (GPCRs) CB1 and CB2 mediate the functional responses to the endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG) and to the widely consumed plant phytocannabinoid Δ9-tetrahydrocannabinol (THC)1. The cannabinoid receptors have been the targets of intensive drug discovery efforts, because modulation of these receptors has therapeutic potential to control pain2, epilepsy3, obesity4, and other disorders. Although much progress in understanding the biophysical properties of GPCRs has recently been made, investigations of the molecular mechanisms of the cannabinoids and their receptors have lacked high-resolution structural data. Here we report the use of GPCR engineering and lipidic cubic phase crystallization to determine the structure of the human CB1 receptor bound to the inhibitor taranabant at 2.6-Å resolution. We found that the extracellular surface of CB1, including the highly conserved membrane-proximal N-terminal region, is distinct from those of other lipid-activated GPCRs, forming a critical part of the ligand-binding pocket. Docking studies further demonstrate how this same pocket may accommodate the cannabinoid agonist THC. Our CB1 structure provides an atomic framework for studying cannabinoid receptor function and will aid the design and optimization of therapeutic modulators of the endocannabinoid system.

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Acknowledgements

We thank the staff of the GM/CA-CAT beamline 23ID at the Advanced Photon Source (APS) for support during data collection. This project was supported by Welch Foundation grant (I-1770 to D.M.R) and a Packard Foundation Fellowship (D.M.R.). APS is a US Department of Energy Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory (DE-AC02-06CH11357).

Author information

Affiliations

  1. Department of Biophysics, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

    • Zhenhua Shao
    • , Jie Yin
    • , Karen Chapman
    • , Magdalena Grzemska
    • , Lindsay Clark
    •  & Daniel M. Rosenbaum
  2. Green Center for Systems Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

    • Junmei Wang

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Contributions

Z.S. developed the CB1 construct and purification; expressed, purified and crystallized the receptor; collected diffraction data; and solved and refined the structure. J.Y. assisted with crystallographic refinement. K.C. performed ligand binding assays on CB1 constructs. M.G. carried out computational docking calculations. L.C. assisted with construct design and purification. J.W. performed and supervised computational docking calculations and molecular dynamics simulations. D.M.R supervised the overall project, assisted with collection of diffraction data, and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Daniel M. Rosenbaum.

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

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https://doi.org/10.1038/nature20613

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