8WU1

Cryo-EM structure of CB1-beta-arrestin1 complex

Summary for 8WU1

• Entry DOI: 10.2210/pdb8wu1/pdb
• EMDB information: 37849
• Descriptor: Beta-arrestin-1, Fab30 heavy chain, Fab30 light chain, ... (5 entities in total)
• Functional Keywords: cannabinoid receptor, arrestin, biased signal, class a gpcr, membrane protein
• Biological source: Bos taurus (cattle); More
• Total number of polymer chains: 4
• Total formula weight: 143928.41

Authors

Liao, Y.,Zhang, H.,Shen, Q.,Cai, C. (deposition date: 2023-10-19, release date: 2024-03-20, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (3.2 Å)