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.
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 (2019). Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex. Cell, 176(3). https://doi.org/10.1016/j.cell.2018.11.040
Kumar, Kaavya Krishna, Shalev-Benami, Moran, Robertson, Michael J., et al., "Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex," Cell 176, no. 3 (2019), https://doi.org/10.1016/j.cell.2018.11.040
@article{osti_1503451,
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 others},
title = {Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex},
annote = {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},
url = {https://www.osti.gov/biblio/1503451},
journal = {Cell},
issn = {ISSN 0092-8674},
number = {3},
volume = {176},
place = {United States},
publisher = {Elsevier},
year = {2019},
month = {01}}