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-Structure paper
タイトル | Molecular mechanism of allosteric modulation for the cannabinoid receptor CB1. |
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ジャーナル・号・ページ | Nat Chem Biol, Vol. 18, Issue 8, Page 831-840, Year 2022 |
掲載日 | 2022年5月30日 |
著者 | 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 / |
PubMed 要旨 | 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 ...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. |
リンク | Nat Chem Biol / PubMed:35637350 |
手法 | EM (単粒子) / X線回折 |
解像度 | 2.7 - 3.36 Å |
構造データ | EMDB-32850, PDB-7wv9: PDB-7fee: |
化合物 | ChemComp-CLR: ChemComp-9GF: ChemComp-7IC: ChemComp-PEG: ChemComp-GOL: ChemComp-OLC: ChemComp-OLA: ChemComp-HOH: |
由来 |
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キーワード | MEMBRANE PROTEIN / signal protein / GPCR / Complex / agonist |