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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. © 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.


Xin Yang, Xuehui Wang, Zheng Xu, Chao Wu, Yangli Zhou, Yifei Wang, Guifeng Lin, Kan Li, Ming Wu, Anjie Xia, Jingming Liu, Lin Cheng, Jun Zou, Wei Yan, Zhenhua Shao, Shengyong Yang. Molecular mechanism of allosteric modulation for the cannabinoid receptor CB1. Nature chemical biology. 2022 Aug;18(8):831-840

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PMID: 35637350

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