中国科学院上海药物研究所徐华强等研究人员合作报道人类μ-阿片受体对吗啡和芬太尼的分子识别。2022年11月10日出版的《细胞》杂志发表了这项成果。

研究人员报告了与吗啡和芬太尼结合的人类μ-阿片受体（μOR）-G蛋白复合物的结构，并揭示了它们如何与受体结合的关键差异。研究人员还报告了μOR与TRV130、PZM21和SR17018结合的结构，并揭示了这些激动剂与配体结合袋的TM3侧而不是TM6/7侧的优先相互作用。相反，吗啡和芬太尼与TM3和TM6/7区域形成双重相互作用。TM6/7界面的突变废除了吗啡和芬太尼促进的阻遏蛋白对μOR的招募。旨在减少TM6/7相互作用的配体显示出优先的G蛋白信号传导。

这些研究结果为芬太尼对μOR的识别和信号传导提供了关键的见解，这可能有助于合理设计下一代镇痛药。

据了解，吗啡和芬太尼是最常用的阿片类药物之一，它们通过μOR的G蛋白和阻遏蛋白信号通路赋予镇痛和不必要的副作用。

附：英文原文

Title: Molecular recognition of morphine and fentanyl by the human μ-opioid receptor

Author: Youwen Zhuang, Yue Wang, Bingqing He, Xinheng He, X. Edward Zhou, Shimeng Guo, Qidi Rao, Jiaqi Yang, Jinyu Liu, Qingtong Zhou, Xiaoxi Wang, Mingliang Liu, Weiyi Liu, Xiangrui Jiang, Dehua Yang, Hualiang Jiang, Jingshan Shen, Karsten Melcher, Hong Chen, Yi Jiang, Xi Cheng, Ming-Wei Wang, Xin Xie, H. Eric Xu

Issue&Volume: 2022/11/10

Abstract: Morphine and fentanyl are among the most used opioid drugs that confer analgesia and unwanted side effects through both G protein and arrestin signaling pathways of μ-opioid receptor (μOR). Here, we report structures of the human μOR-G protein complexes bound to morphine and fentanyl, which uncover key differences in how they bind the receptor. We also report structures of μOR bound to TRV130, PZM21, and SR17018, which reveal preferential interactions of these agonists with TM3 side of the ligand-binding pocket rather than TM6/7 side. In contrast, morphine and fentanyl form dual interactions with both TM3 and TM6/7 regions. Mutations at the TM6/7 interface abolish arrestin recruitment of μOR promoted by morphine and fentanyl. Ligands designed to reduce TM6/7 interactions display preferential G protein signaling. Our results provide crucial insights into fentanyl recognition and signaling of μOR, which may facilitate rational design of next-generation analgesics.

DOI: 10.1016/j.cell.2022.09.041

Source: https://www.cell.com/cell/fulltext/S0092-8674(22)01260-0