Abstract：
Cannabis activates the cannabinoid receptor 1 (CB1), which elicits analgesic and emotion regulation benefits, along with adverse effects, via Gi 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 Gi 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 Gi-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.
摘要：
大麻激活大麻素受体1（CB1），这引发了镇痛和情绪调节的好处，伴随着不良影响，通过Gi和β-抑制蛋白信号通路。然而,对β-arrestin-1(βarr1)偶联机制的认识不足和信号传导偏倚阻碍了靶向CB1的药物开发.这里,我们介绍了与合成大麻素MDMB-Fubinaca（FUB）结合的CB1-βarr1复合物的高分辨率低温电子显微镜结构，揭示了与Gi蛋白复合物相比，换能器袋和配体结合位点的显着差异。βarr1占据较宽的换能器袋，促进TM6的大量向外移动和独特的双拨动开关重排，而FUB采用不同的姿势，插入比Gi耦合状态更深，表明正构结合口袋和伴侣蛋白位点之间的变构相关性。一起来看,我们的研究结果揭示了信号传导偏向CB1的分子机制,促进了CB1激动剂的发展.
