Format

Send to

Choose Destination
Nature. 2017 Jul 27;547(7664):468-471. doi: 10.1038/nature23272. Epub 2017 Jul 5.

Crystal structures of agonist-bound human cannabinoid receptor CB1.

Author information

1
iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
2
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
3
University of Chinese Academy of Sciences, Beijing 100049, China.
4
Center for Drug Discovery, Department of Pharmaceutical Sciences; Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, USA.
5
Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute, Jupiter, Florida 33458, USA.
6
Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.
7
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
8
Complex Systems Division, Beijing Computational Science Research Center, Beijing 100193, China.
9
GPCR Consortium, San Marcos, California 92078, USA.

Abstract

The cannabinoid receptor 1 (CB1) is the principal target of the psychoactive constituent of marijuana, the partial agonist Δ9-tetrahydrocannabinol (Δ9-THC). 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 state, 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 numbering) 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.

PMID:
28678776
PMCID:
PMC5793864
DOI:
10.1038/nature23272
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center