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 L. Farrens; Ron O. Dror; Sanjay V. Malhotra; Brian K. Kobilka; Georgios Skiniotis

doi:10.1016/j.cell.2018.11.040

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 L. Farrens, Ron O. Dror, Sanjay V. Malhotra, Brian K. Kobilka, Georgios Skiniotis

Chemical Physiology and Biochemistry

Research output: Contribution to journal › Article › peer-review

277 Scopus citations

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 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. 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 language	English (US)
Pages (from-to)	448-458.e12
Journal	Cell
Volume	176
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2018.11.040
State	Published - Jan 24 2019

Keywords

CB1
Fubinaca
G
GPCR
cannabinoid receptor
cryo-EM
synthetic cannabinoid

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.cell.2018.11.040

Cite this

Krishna Kumar, K., Shalev-Benami, M., Robertson, M. J., Hu, H., Banister, S. D., Hollingsworth, S. A., Latorraca, N. R., Kato, H. E., Hilger, D., Maeda, S., Weis, W. I., Farrens, D. L., Dror, R. O., Malhotra, S. V., Kobilka, B. K., & 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

@article{207ff70ee7c84d6bb974a2222aae5815,

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. 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, GPCR, cannabinoid receptor, cryo-EM, synthetic cannabinoid",

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

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2019",

month = jan,

day = "24",

doi = "10.1016/j.cell.2018.11.040",

language = "English (US)",

volume = "176",

pages = "448--458.e12",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "3",

}

TY - JOUR

T1 - Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex

AU - Krishna Kumar, Kaavya

AU - Shalev-Benami, Moran

AU - Robertson, Michael J.

AU - Hu, Hongli

AU - Banister, Samuel D.

AU - Hollingsworth, Scott A.

AU - Latorraca, Naomi R.

AU - Kato, Hideaki E.

AU - Hilger, Daniel

AU - Maeda, Shoji

AU - Weis, William I.

AU - Farrens, David L.

AU - Dror, Ron O.

AU - Malhotra, Sanjay V.

AU - Kobilka, Brian K.

AU - Skiniotis, Georgios

PY - 2019/1/24

Y1 - 2019/1/24

N2 - 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.

AB - 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.

KW - CB1

KW - Fubinaca

KW - G

KW - GPCR

KW - cannabinoid receptor

KW - cryo-EM

KW - synthetic cannabinoid

UR - http://www.scopus.com/inward/record.url?scp=85059821238&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059821238&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2018.11.040

DO - 10.1016/j.cell.2018.11.040

M3 - Article

C2 - 30639101

AN - SCOPUS:85059821238

SN - 0092-8674

VL - 176

SP - 448-458.e12

JO - Cell

JF - Cell

IS - 3

ER -

Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this