TY - JOUR
T1 - Structure of an allosteric modulator bound to the CB1 cannabinoid receptor
AU - Shao, Zhenhua
AU - Yan, Wei
AU - Chapman, Karen
AU - Ramesh, Karthik
AU - Ferrell, Aaron J.
AU - Yin, Jie
AU - Wang, Xuehui
AU - Xu, Qingping
AU - Rosenbaum, Daniel M.
N1 - Funding Information:
We thank the staff of the GM/CA-CAT beamline 23ID at the Advanced Photon Source for support during data collection. This project was supported by the Edward Mallinckrodt, Jr. Foundation (Scholar Award to D.M.R.), the Welch Foundation (grant no. I-1770 to D.M.R.) and the National Young Thousand Talents Program of China (to Z.S.). APS is a US Department of Energy Office of Science User Facility operated for the Department of Energy Office of Science by Argonne National Laboratory (no. DE-AC02-06CH11357).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41589-019-0387-2
DO - 10.1038/s41589-019-0387-2
M3 - Article
C2 - 31659318
AN - SCOPUS:85074637157
SN - 1552-4450
VL - 15
SP - 1199
EP - 1205
JO - Nature chemical biology
JF - Nature chemical biology
IS - 12
ER -