| http://purl.uniprot.org/citations/35637350 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/35637350 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/35637350 | http://www.w3.org/2000/01/rdf-schema#comment | "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."xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.org/dc/terms/identifier | "doi:10.1038/s41589-022-01038-y"xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.org/dc/terms/identifier | "doi:10.1038/s41589-022-01038-y"xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.uniprot.org/core/author | "Cheng L."xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.uniprot.org/core/author | "Cheng L."xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.uniprot.org/core/author | "Li K."xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.uniprot.org/core/author | "Li K."xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.uniprot.org/core/author | "Liu J."xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.uniprot.org/core/author | "Liu J."xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.uniprot.org/core/author | "Wu M."xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.uniprot.org/core/author | "Wu M."xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.uniprot.org/core/author | "Wang Y."xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.uniprot.org/core/author | "Wang Y."xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.uniprot.org/core/author | "Shao Z."xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.uniprot.org/core/author | "Shao Z."xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.uniprot.org/core/author | "Yang X."xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.uniprot.org/core/author | "Yang X."xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.uniprot.org/core/author | "Wang X."xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.uniprot.org/core/author | "Wang X."xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.uniprot.org/core/author | "Yan W."xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.uniprot.org/core/author | "Yan W."xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.uniprot.org/core/author | "Zhou Y."xsd:string |
| http://purl.uniprot.org/citations/35637350 | http://purl.uniprot.org/core/author | "Zhou Y."xsd:string |