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

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. 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.

Authors:
 [1];  [1];  [1];  [1];  [1];  [2];  [2];  [1];  [1];  [1];  [3];  [4];  [2];  [1];  [1];  [3]
  1. Stanford Univ. School of Medicine, Stanford, CA (United States)
  2. Stanford Univ. School of Medicine, Stanford, CA (United States); Stanford Univ., Stanford, CA (United States)
  3. Stanford Univ. School of Medicine, Stanford, CA (United States); Stanford Univ., Menlo Park, CA (United States). SLAC National Accelerator Lab
  4. Oregon Health Sciences Univ., Portland, OR (United States)
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1503451
Grant/Contract Number:  
AC02-76SF00515; R37DA036246; R01GM083118
Resource Type:
Accepted Manuscript
Journal Name:
Cell
Additional Journal Information:
Journal Volume: 176; Journal Issue: 3; Journal ID: ISSN 0092-8674
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; cannabinoid receptor; CB1; GPCR; cryo-EM; synthetic cannabinoid; Fubinaca; Gi

Citation Formats

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., and Skiniotis, Georgios. Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex. United States: N. p., 2019. Web. doi:10.1016/j.cell.2018.11.040.
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. Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex. United States. https://doi.org/10.1016/j.cell.2018.11.040
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., and Skiniotis, Georgios. Thu . "Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex". United States. https://doi.org/10.1016/j.cell.2018.11.040. https://www.osti.gov/servlets/purl/1503451.
@article{osti_1503451,
title = {Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex},
author = {Kumar, Kaavya Krishna and Shalev-Benami, Moran and Robertson, Michael J. and Hu, Hongli and Banister, Samuel D. and Hollingsworth, Scott A. and Latorraca, Naomi R. and Kato, Hideaki E. and Hilger, Daniel and Maeda, Shoji and Weis, William I. and Farrens, David L. and Dror, Ron O. and Malhotra, Sanjay V. and Kobilka, Brian K. and Skiniotis, Georgios},
abstractNote = {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. 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.},
doi = {10.1016/j.cell.2018.11.040},
journal = {Cell},
number = 3,
volume = 176,
place = {United States},
year = {2019},
month = {1}
}

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