Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex

Kumar, Kaavya Krishna; Shalev-Benami, Moran; Robertson, Michael J.; Hu, Hongli; Banister, Samuel D.; Hollingsworth, Scott A.; Latorraca, Naomi R.; Kato, Hideaki E.; Hilger, Daniel; Maeda, Shoji; Weis, William I.; Farrens, David L.; Dror, Ron O.; Malhotra, Sanjay V.; Kobilka, Brian K.; Skiniotis, Georgios

doi:10.1016/j.cell.2018.11.040

Title: Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex

Journal Article · Thu Jan 10 00:00:00 EST 2019 · Cell

DOI:https://doi.org/10.1016/j.cell.2018.11.040· OSTI ID:1503451

Kumar, Kaavya Krishna ^[1]; Shalev-Benami, Moran ^[1]; Robertson, Michael J. ^[1]; Hu, Hongli ^[1]; Banister, Samuel D. ^[1]; Hollingsworth, Scott A. ^[2]; Latorraca, Naomi R. ^[2]; Kato, Hideaki E. ^[1]; Hilger, Daniel ^[1]; Maeda, Shoji ^[1]; Weis, William I. ^[3]; Farrens, David L. ^[4]; Dror, Ron O. ^[2]; Malhotra, Sanjay V. ^[1]; Kobilka, Brian K. ^[1]; Skiniotis, Georgios ^[3]

Stanford Univ. School of Medicine, Stanford, CA (United States)
Stanford Univ. School of Medicine, Stanford, CA (United States); Stanford Univ., Stanford, CA (United States)
Stanford Univ. School of Medicine, Stanford, CA (United States); Stanford Univ., Menlo Park, CA (United States). SLAC National Accelerator Lab
Oregon Health Sciences Univ., Portland, OR (United States)

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 G_i. Activation of CB1-G_i signaling pathways holds potential for treating a number of neurological disorders and is thus crucial to understand the mechanism of G_i activation by CB1. Here, we present the structure of the CB1-G_i 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 G_i. Furthermore 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.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-76SF00515; R37DA036246; R01GM083118

OSTI ID:: 1503451

Journal Information:: Cell, Vol. 176, Issue 3; ISSN 0092-8674

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 225 works

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In vitro determination of the efficacy of illicit synthetic cannabinoids at CB ₁ receptors Sachdev, Shivani; Vemuri, Kiran; Banister, Samuel D. British Journal of Pharmacology, Vol. 176, Issue 24 https://doi.org/10.1111/bph.14829	journal	December 2019
Structure of an allosteric modulator bound to the CB1 cannabinoid receptor Shao, Zhenhua; Yan, Wei; Chapman, Karen Nature Chemical Biology, Vol. 15, Issue 12 https://doi.org/10.1038/s41589-019-0387-2	journal	October 2019
Control of glutamate release by complexes of adenosine and cannabinoid receptors Köfalvi, Attila; Moreno, Estefanía; Cordomí, Arnau BMC Biology, Vol. 18, Issue 1 https://doi.org/10.1186/s12915-020-0739-0	journal	January 2020
Adding more “spice” to the pot: A review of the chemistry and pharmacology of newly emerging heterocyclic synthetic cannabinoid receptor agonists Alam, Ryan M.; Keating, John J. Drug Testing and Analysis, Vol. 12, Issue 3 https://doi.org/10.1002/dta.2752	journal	January 2020

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59 BASIC BIOLOGICAL SCIENCES
cannabinoid receptor
CB1
GPCR
cryo-EM
synthetic cannabinoid
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Title: Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex

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