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Cell. 2019 Jan 24;176(3):448-458.e12. doi: 10.1016/j.cell.2018.11.040. Epub 2019 Jan 10.

Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex.

Author information

1
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA.
2
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA.
3
Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University School of Medicine, Stanford, CA 94304, USA.
4
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA; Biophysics Program, Stanford University, Stanford, CA 94305, USA.
5
Department of Structural Biology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA; Department of Photon Science, SLAC National Accelerator Laboratory, Stanford University, Menlo Park, CA 94025, USA.
6
Departments of Biochemistry and Molecular Biology, Oregon Health Sciences University, Portland, OR 97201, USA.
7
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA. Electronic address: kobilka@stanford.edu.
8
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA 94305, USA; Department of Photon Science, SLAC National Accelerator Laboratory, Stanford University, Menlo Park, CA 94025, USA. Electronic address: yiorgo@stanford.edu.

Abstract

Cannabis elicits its mood-enhancing and analgesic effects through the cannabinoid receptor 1 (CB1), a G protein-coupled receptor (GPCR) that signals primarily through the adenylyl cyclase-inhibiting heterotrimeric G protein Gi. Activation of CB1-Gi signaling pathways holds potential for treating a number of neurological disorders and is thus crucial to understand the mechanism of Gi activation by CB1. Here, we present the structure of the CB1-Gi signaling complex bound to the highly potent agonist MDMB-Fubinaca (FUB), a recently emerged illicit synthetic cannabinoid infused in street drugs that have been associated with numerous overdoses and fatalities. The structure illustrates how FUB stabilizes the receptor in an active state to facilitate nucleotide exchange in Gi. The results compose the structural framework to explain CB1 activation by different classes of ligands and provide insights into the G protein coupling and selectivity mechanisms adopted by the receptor.

KEYWORDS:

CB1; Fubinaca; G(i); GPCR; cannabinoid receptor; cryo-EM; synthetic cannabinoid

PMID:
30639101
DOI:
10.1016/j.cell.2018.11.040

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