Molecular mechanism of allosteric modulation for the cannabinoid receptor CB1.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
15
09
2021
accepted:
13
04
2022
pubmed:
1
6
2022
medline:
3
8
2022
entrez:
31
5
2022
Statut:
ppublish
Résumé
Given the promising clinical value of allosteric modulators of G protein-coupled-receptors (GPCRs), mechanistic understanding of how these modulators alter GPCR function is of significance. Here, we report the crystallographic and cryo-electron microscopy structures of the cannabinoid receptor CB1 bound to the positive allosteric modulator (PAM) ZCZ011. These structures show that ZCZ011 binds to an extrahelical site in the transmembrane 2 (TM2)-TM3-TM4 surface. Through (un)biased molecular dynamics simulations and mutagenesis experiments, we show that TM2 rearrangement is critical for the propagation of allosteric signals. ZCZ011 exerts a PAM effect by promoting TM2 rearrangement in favor of receptor activation and increasing the population of receptors that adopt an active conformation. In contrast, ORG27569, a negative allosteric modulator (NAM) of CB1, also binds to the TM2-TM3-TM4 surface and exerts a NAM effect by impeding the TM2 rearrangement. Our findings fill a gap in the understanding of CB1 allosteric regulation and could guide the rational design of CB1 allosteric modulators.
Identifiants
pubmed: 35637350
doi: 10.1038/s41589-022-01038-y
pii: 10.1038/s41589-022-01038-y
doi:
Substances chimiques
Receptor, Cannabinoid, CB1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
831-840Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
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