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

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

doi:10.1016/j.cell.2022.09.041

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.

Authors

Youwen Zhuang¹, Yue Wang², Bingqing He³, Xinheng He², X Edward Zhou⁴, Shimeng Guo⁵, Qidi Rao⁶, Jiaqi Yang⁷, Jinyu Liu⁸, Qingtong Zhou⁹, Xiaoxi Wang⁷, Mingliang Liu⁷, Weiyi Liu², Xiangrui Jiang², Dehua Yang¹⁰, Hualiang Jiang¹¹, Jingshan Shen², Karsten Melcher⁴, Hong Chen¹², Yi Jiang², Xi Cheng², Ming-Wei Wang¹³, Xin Xie¹⁴, H Eric Xu¹⁵

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.

PMID: 36368306
DOI: 10.1016/j.cell.2022.09.041

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Analgesics, Opioid / pharmacology
Arrestin / metabolism
Fentanyl* / pharmacology
GTP-Binding Proteins / metabolism
Humans
Morphine* / pharmacology
Receptors, Opioid, mu

Substances

Analgesics, Opioid
Arrestin
Fentanyl
GTP-Binding Proteins
Morphine
Receptors, Opioid, mu