Structure of an allosteric modulator bound to the CB1 cannabinoid receptor
Abstract
The CB1 receptor mediates the central nervous system response to cannabinoids, and is a drug target for pain, anxiety and seizures. CB1 also responds to allosteric modulators, which influence cannabinoid binding and efficacy. To understand the mechanism of these compounds, we solved the crystal structure of CB1 with the negative allosteric modulator (NAM) ORG27569 and the agonist CP55940. The structure reveals that the NAM binds to an extrahelical site within the inner leaflet of the membrane, which overlaps with a conserved site of cholesterol interaction in many G protein-coupled receptors (GPCRs). The ternary structure with ORG27569 and CP55940 captures an intermediate state of the receptor, in which aromatic residues at the base of the agonist-binding pocket adopt an inactive conformation despite the large contraction of the orthosteric pocket. The structure illustrates a potential strategy for drug modulation of CB1 and other class A GPCRs.
- Authors:
-
[1];
[2]
- Sichuan Univ., Chengdu (China)
- Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- Welch Foundation; Edward Mallinckrodt, Jr. Foundation; National Young Thousand Talents Program of China; USDOE Office of Science (SC)
- OSTI Identifier:
- 1631989
- Grant/Contract Number:
- AC02-06CH11357; I-1770
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Chemical Biology
- Additional Journal Information:
- Journal Volume: 15; Journal Issue: 12; Journal ID: ISSN 1552-4450
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; GPCR; Structural biology; G protein-coupled receptors; Pharmacology; X-ray crystallography
Citation Formats
Shao, Zhenhua, Yan, Wei, Chapman, Karen, Ramesh, Karthik, Ferrell, Aaron J., Yin, Jie, Wang, Xuehui, Xu, Qingping, and Rosenbaum, Daniel M. Structure of an allosteric modulator bound to the CB1 cannabinoid receptor. United States: N. p., 2019.
Web. doi:10.1038/s41589-019-0387-2.
Shao, Zhenhua, Yan, Wei, Chapman, Karen, Ramesh, Karthik, Ferrell, Aaron J., Yin, Jie, Wang, Xuehui, Xu, Qingping, & Rosenbaum, Daniel M. Structure of an allosteric modulator bound to the CB1 cannabinoid receptor. United States. https://doi.org/10.1038/s41589-019-0387-2
Shao, Zhenhua, Yan, Wei, Chapman, Karen, Ramesh, Karthik, Ferrell, Aaron J., Yin, Jie, Wang, Xuehui, Xu, Qingping, and Rosenbaum, Daniel M. Mon .
"Structure of an allosteric modulator bound to the CB1 cannabinoid receptor". United States. https://doi.org/10.1038/s41589-019-0387-2. https://www.osti.gov/servlets/purl/1631989.
@article{osti_1631989,
title = {Structure of an allosteric modulator bound to the CB1 cannabinoid receptor},
author = {Shao, Zhenhua and Yan, Wei and Chapman, Karen and Ramesh, Karthik and Ferrell, Aaron J. and Yin, Jie and Wang, Xuehui and Xu, Qingping and Rosenbaum, Daniel M.},
abstractNote = {The CB1 receptor mediates the central nervous system response to cannabinoids, and is a drug target for pain, anxiety and seizures. CB1 also responds to allosteric modulators, which influence cannabinoid binding and efficacy. To understand the mechanism of these compounds, we solved the crystal structure of CB1 with the negative allosteric modulator (NAM) ORG27569 and the agonist CP55940. The structure reveals that the NAM binds to an extrahelical site within the inner leaflet of the membrane, which overlaps with a conserved site of cholesterol interaction in many G protein-coupled receptors (GPCRs). The ternary structure with ORG27569 and CP55940 captures an intermediate state of the receptor, in which aromatic residues at the base of the agonist-binding pocket adopt an inactive conformation despite the large contraction of the orthosteric pocket. The structure illustrates a potential strategy for drug modulation of CB1 and other class A GPCRs.},
doi = {10.1038/s41589-019-0387-2},
journal = {Nature Chemical Biology},
number = 12,
volume = 15,
place = {United States},
year = {Mon Oct 28 00:00:00 EDT 2019},
month = {Mon Oct 28 00:00:00 EDT 2019}
}
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