7FEE

Crystal structure of the allosteric modulator ZCZ011 binding to CP55940-bound cannabinoid receptor 1

7FEE の概要

• エントリーDOI: 10.2210/pdb7fee/pdb
• 分子名称: Cannabinoid receptor 1,GlgA glycogen synthase, CHOLESTEROL, 2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol, ... (9 entities in total)
• 機能のキーワード: signal protein, membrane protein, gpcr
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 67500.21

構造登録者

Wang, X.,Zhao, C.,Shao, Z. (登録日: 2021-07-19, 公開日: 2022-06-15, 最終更新日: 2024-10-23)

主引用文献

Yang, X.,Wang, X.,Xu, Z.,Wu, C.,Zhou, Y.,Wang, Y.,Lin, G.,Li, K.,Wu, M.,Xia, A.,Liu, J.,Cheng, L.,Zou, J.,Yan, W.,Shao, Z.,Yang, S.
Molecular mechanism of allosteric modulation for the cannabinoid receptor CB1.
Nat.Chem.Biol., 18:831-840, 2022

PubMed 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.

PubMed: 35637350
DOI: 10.1038/s41589-022-01038-y

実験手法

X-RAY DIFFRACTION (2.7 Å)