| Literature DB >> 35637350 |
Xin Yang1, Xuehui Wang1,2, Zheng Xu1,2, Chao Wu1,2, Yangli Zhou1, Yifei Wang1, Guifeng Lin1, Kan Li1, Ming Wu1, Anjie Xia1, Jingming Liu1, Lin Cheng1,2, Jun Zou1, Wei Yan1,2, Zhenhua Shao3,4, Shengyong Yang5.
Abstract
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.Entities:
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Year: 2022 PMID： 35637350 DOI： 10.1038/s41589-022-01038-y
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 16.174