8WU1

Cryo-EM structure of CB1-beta-arrestin1 complex

8WU1 の概要

• エントリーDOI: 10.2210/pdb8wu1/pdb
• EMDBエントリー: 37849
• 分子名称: Beta-arrestin-1, Fab30 heavy chain, Fab30 light chain, ... (5 entities in total)
• 機能のキーワード: cannabinoid receptor, arrestin, biased signal, class a gpcr, membrane protein
• 由来する生物種: Bos taurus (cattle); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 143928.41

構造登録者

Liao, Y.,Zhang, H.,Shen, Q.,Cai, C. (登録日: 2023-10-19, 公開日: 2024-03-20, 最終更新日: 2024-10-16)

主引用文献

Liao, Y.Y.,Zhang, H.,Shen, Q.,Cai, C.,Ding, Y.,Shen, D.D.,Guo, J.,Qin, J.,Dong, Y.,Zhang, Y.,Li, X.M.
Snapshot of the cannabinoid receptor 1-arrestin complex unravels the biased signaling mechanism.
Cell, 186:5784-5797.e17, 2023

PubMed Abstract: Cannabis activates the cannabinoid receptor 1 (CB1), which elicits analgesic and emotion regulation benefits, along with adverse effects, via G and β-arrestin signaling pathways. However, the lack of understanding of the mechanism of β-arrestin-1 (βarr1) coupling and signaling bias has hindered drug development targeting CB1. Here, we present the high-resolution cryo-electron microscopy structure of CB1-βarr1 complex bound to the synthetic cannabinoid MDMB-Fubinaca (FUB), revealing notable differences in the transducer pocket and ligand-binding site compared with the G protein complex. βarr1 occupies a wider transducer pocket promoting substantial outward movement of the TM6 and distinctive twin toggle switch rearrangements, whereas FUB adopts a different pose, inserting more deeply than the G-coupled state, suggesting the allosteric correlation between the orthosteric binding pocket and the partner protein site. Taken together, our findings unravel the molecular mechanism of signaling bias toward CB1, facilitating the development of CB1 agonists.

PubMed: 38101408
DOI: 10.1016/j.cell.2023.11.017

実験手法

ELECTRON MICROSCOPY (3.2 Å)