吗啡和芬太尼与人 μ 阿片受体的分子识别。
Molecular recognition of morphine and fentanyl by the human μ-opioid receptor.
机构信息
The CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
The CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
出版信息
Cell. 2022 Nov 10;185(23):4361-4375.e19. doi: 10.1016/j.cell.2022.09.041.
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.
吗啡和芬太尼是最常使用的阿片类药物之一，它们通过 μ 型阿片受体（μOR）的 G 蛋白和抑制蛋白信号通路发挥镇痛作用和产生不良反应。在这里，我们报告了与吗啡和芬太尼结合的人 μOR-G 蛋白复合物的结构，这些结构揭示了它们与受体结合的关键差异。我们还报告了 μOR 与 TRV130、PZM21 和 SR17018 结合的结构，这些结构揭示了这些激动剂与配体结合口袋的 TM3 侧而非 TM6/7 侧优先相互作用。相比之下，吗啡和芬太尼与 TM3 和 TM6/7 区域同时形成双重相互作用。TM6/7 界面的突变会消除吗啡和芬太尼促进的 μOR 抑制蛋白募集。设计用于减少 TM6/7 相互作用的配体显示出对 G 蛋白信号的偏好。我们的研究结果为芬太尼对 μOR 的识别和信号转导提供了重要的见解，这可能有助于合理设计下一代阿片类镇痛药。
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