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TitleSnapshot of the cannabinoid receptor 1-arrestin complex unravels the biased signaling mechanism.
Journal, issue, pagesCell, Vol. 186, Issue 26, Page 5784-5797.e17, Year 2023
Publish dateDec 21, 2023
AuthorsYu-Ying Liao / Huibing Zhang / Qingya Shen / Chenxi Cai / Yu Ding / Dan-Dan Shen / Jia Guo / Jiao Qin / Yingjun Dong / Yan Zhang / Xiao-Ming Li /
PubMed AbstractCannabis 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 ...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.
External linksCell / PubMed:38101408
MethodsEM (single particle)
Resolution3.2 Å
Structure data

37849

8wu1

EMDB-37849, PDB-8wu1:
Cryo-EM structure of CB1-beta-arrestin1 complex
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-KCA:
methyl N-{1-[(4-fluorophenyl)methyl]-1H-indazole-3-carbonyl}-3-methyl-L-valinate / agonist*YM

Source
  • bos taurus (domestic cattle)
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / cannabinoid receptor / arrestin / biased signal / class A GPCR

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