Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex

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

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)448-458.e12
JournalCell
Volume176
Issue number3
DOIs
StatePublished - Jan 24 2019

Fingerprint

Cannabinoid Receptors
GTP-Binding Proteins
Chemical activation
Heterotrimeric GTP-Binding Proteins
Cannabinoids
Street Drugs
Cannabis
G-Protein-Coupled Receptors
Nervous System Diseases
Adenylyl Cyclases
Analgesics
Nucleotides
Ligands

Keywords

  • cannabinoid receptor
  • CB1
  • cryo-EM
  • Fubinaca
  • G
  • GPCR
  • synthetic cannabinoid

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Krishna Kumar, K., Shalev-Benami, M., Robertson, M. J., Hu, H., Banister, S. D., Hollingsworth, S. A., ... Skiniotis, G. (2019). Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex. Cell, 176(3), 448-458.e12. https://doi.org/10.1016/j.cell.2018.11.040

Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex. / Krishna Kumar, Kaavya; 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; Dror, Ron O.; Malhotra, Sanjay V.; Kobilka, Brian K.; Skiniotis, Georgios.

In: Cell, Vol. 176, No. 3, 24.01.2019, p. 448-458.e12.

Research output: Contribution to journalArticle

Krishna Kumar, K, Shalev-Benami, M, Robertson, MJ, Hu, H, Banister, SD, Hollingsworth, SA, Latorraca, NR, Kato, HE, Hilger, D, Maeda, S, Weis, WI, Farrens, D, Dror, RO, Malhotra, SV, Kobilka, BK & Skiniotis, G 2019, 'Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex', Cell, vol. 176, no. 3, pp. 448-458.e12. https://doi.org/10.1016/j.cell.2018.11.040
Krishna Kumar K, Shalev-Benami M, Robertson MJ, Hu H, Banister SD, Hollingsworth SA et al. Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex. Cell. 2019 Jan 24;176(3):448-458.e12. https://doi.org/10.1016/j.cell.2018.11.040
Krishna Kumar, Kaavya ; 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 ; Dror, Ron O. ; Malhotra, Sanjay V. ; Kobilka, Brian K. ; Skiniotis, Georgios. / Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex. In: Cell. 2019 ; Vol. 176, No. 3. pp. 448-458.e12.
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