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Molecular mechanism of allosteric modulation for the cannabinoid receptor CB1.

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作者：
Yang Xin[1] * ; Wang Xuehui[1,2] * ; Xu Zheng[1,2] * ; Wu Chao[1,2] * ; Zhou Yangli[1] ; Wang Yifei[1] ; Lin Guifeng[1] ; Li Kan[1] ; Wu Ming[1] ; Xia Anjie[1] ; Liu Jingming[1] ; Cheng Lin[1,2] ; Zou Jun[1] ; Yan Wei[1,2] ; Shao Zhenhua[1,2] ; Yang Shengyong[1] ;
机构： [1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [2]Division of Nephrology and Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
出处：
DOI： 10.1038/s41589-022-01038-y
ISSN：

摘要：
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.

基金：
This work was supported by the National Natural Science Foundation of China (31972916, 81930125, 82130104, 32100988), Science and Technology Department of Sichuan Province 2020YJ0208 (Z.S.), 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYYC20023, ZYGD18001, ZYXY21001). Science and Technology Department of Chengdu (2019-YF05-00294-SN to Z.S.). We thank staff of the BL18U beamline at National Center for Protein Sciences Shanghai (NCPSS) and BL32XU beamline of Spring-8. The diffraction data collection was performed at the BL32XU of Spring-8 with approval of the Japan Synchrotron Radiation Research Institute (JASRI) (proposal number 2019B2705). We thank J. Giraldo for providing MD-generated receptor conformations at the beginning of the project. This research used resources from the Duyu High Performance Computing Center, Sichuan University, and Big Data Platform at West China Hospital of Sichuan University (WCH-BDP).
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出版当年[2022]版：
大类 | 1 区 生物学
小类 | 1 区 生化与分子生物学
最新[2023]版：
大类 | 1 区 生物学
小类 | 1 区 生化与分子生物学
第一作者：
第一作者机构： [1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
共同第一作者：
通讯作者：
通讯机构： [1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [2]Division of Nephrology and Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
推荐引用方式(GB/T 7714)：
Yang Xin,Wang Xuehui,Xu Zheng,et al.Molecular mechanism of allosteric modulation for the cannabinoid receptor CB1.[J].Nature chemical biology.2022,doi:10.1038/s41589-022-01038-y.
APA：
Yang Xin,Wang Xuehui,Xu Zheng,Wu Chao,Zhou Yangli...&Yang Shengyong.(2022).Molecular mechanism of allosteric modulation for the cannabinoid receptor CB1..Nature chemical biology,,
MLA：
Yang Xin,et al."Molecular mechanism of allosteric modulation for the cannabinoid receptor CB1.".Nature chemical biology .(2022)

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