1. Academic Validation
  2. Molecular recognition of morphine and fentanyl by the human μ-opioid receptor

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

  • Cell. 2022 Nov 10;185(23):4361-4375.e19. doi: 10.1016/j.cell.2022.09.041.
Youwen Zhuang 1 Yue Wang 2 Bingqing He 3 Xinheng He 2 X Edward Zhou 4 Shimeng Guo 5 Qidi Rao 6 Jiaqi Yang 7 Jinyu Liu 8 Qingtong Zhou 9 Xiaoxi Wang 7 Mingliang Liu 7 Weiyi Liu 2 Xiangrui Jiang 2 Dehua Yang 10 Hualiang Jiang 11 Jingshan Shen 2 Karsten Melcher 4 Hong Chen 12 Yi Jiang 2 Xi Cheng 2 Ming-Wei Wang 13 Xin Xie 14 H Eric Xu 15
Affiliations

Affiliations

  • 1 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. Electronic address: zhuangyouwen@simm.ac.cn.
  • 2 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.
  • 3 University of Chinese Academy of Sciences, Beijing 100049, China; The State Key Laboratory of Drug Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 4 Department of Structural Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
  • 5 University of Chinese Academy of Sciences, Beijing 100049, China; The State Key Laboratory of Drug Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China.
  • 6 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 7 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.
  • 8 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China.
  • 9 Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • 10 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; The State Key Laboratory of Drug Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 11 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; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 12 Shanghai Key Laboratory of Crime Scene Evidence, Shanghai Research Institute of Criminal Science and Technology, Shanghai 200083, China; Shanghai Yuansi Standard Science and Technology Co., Ltd, Shanghai 200080, China.
  • 13 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; The State Key Laboratory of Drug Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: mwwang@simm.ac.cn.
  • 14 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; The State Key Laboratory of Drug Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China. Electronic address: xxie@simm.ac.cn.
  • 15 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. Electronic address: eric.xu@simm.ac.cn.
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.

Keywords

analgesic; biased G protein signaling; cryo-EM; drug design; fentanyl; fentanyl derivatives; morphine; opioid receptors; partial agonism; μOR.

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