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

doi:10.1016/j.cell.2022.09.041

	Molecular recognition of morphine and fentanyl by the human mu-opioid receptor
	Zhuang, Youwen 1; Wang, Yue 1,2; He, Bingqing2,3,4 ; He, Xinheng 1,2; Zhou, X. Edward 5; Guo, Shimeng 2,3,6; Rao, Qidi4 ; Yang, Jiaqi 1; Liu, Jinyu 6; Zhou, Qingtong 7; Wang, Xiaoxi 1; Liu, Mingliang 1; Liu, Weiyi 1,2; Jiang, Xiangrui 1,2; Yang, Dehua 1,2,3; Jiang, Hualiang1,2,4 ; Shen, Jingshan 1,2; Melcher, Karsten 5; Chen, Hong 8,9; Jiang, Yi 1,2; Cheng, Xi 1,2; Wang, Ming-Wei1,2,3,4,7 ; Xie, Xin1,2,3,4,6,10 ; Xu, H. Eric 1,2
	2022-11-10
发表期刊	CELL (IF:45.5[JCR-2023],49.0[5-Year])
ISSN	0092-8674
EISSN	1097-4172
卷号	185 期号:23
发表状态	已发表
DOI	10.1016/j.cell.2022.09.041
摘要	Morphine and fentanyl are among the most used opioid drugs that confer analgesia and unwanted side ef-fects through both G protein and arrestin signaling pathways of mu-opioid receptor (mu OR). Here, we report structures of the human mu OR-G protein complexes bound to morphine and fentanyl, which uncover key dif-ferences in how they bind the receptor. We also report structures of mu OR 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 mu OR promoted by morphine and fen-tanyl. Ligands designed to reduce TM6/7 interactions display preferential G protein signaling. Our results provide crucial insights into fentanyl recognition and signaling of mu OR, which may facilitate rational design of next-generation analgesics.
URL	查看原文
收录类别	SCI
语种	英语
资助项目	Ministry of Science and Technology (China)["2018YFA0507000","2018YFA0507002"] ; National Natural Science Foundation of China["82121005","32130022","81730099","81872915","82073904","32171187","81773792","81973373","21704064"] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; CAS Strategic Priority Research Program[XDB37030103] ; National Science &Technology Major Project of China-Key New Drug Creation and Manufacturing Program["2018ZX09735-001","018ZX09711002-002-005"]
WOS研究方向	Biochemistry & Molecular Biology ; Cell Biology
WOS类目	Biochemistry & Molecular Biology ; Cell Biology
WOS记录号	WOS:000900775500003
出版者	CELL PRESS
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/268689
专题	生命科学与技术学院_博士生生命科学与技术学院_特聘教授组_王明伟组免疫化学研究所_特聘教授组_蒋华良组生命科学与技术学院_特聘教授组_谢欣组生命科学与技术学院_硕士生
通讯作者	Zhuang, Youwen; Wang, Ming-Wei; Xie, Xin; Xu, H. Eric
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Struct & Funct Drug Targets, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 5.Van Andel Res Inst, Dept Struct Biol, Grand Rapids, MI 49503 USA 6.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China 7.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 200032, Peoples R China 8.Shanghai Res Inst Criminal Sci & Technol, Shanghai Key Lab Crime Scene Evidence, Shanghai 200083, Peoples R China 9.Shanghai Yuansi Stand Sci & Technol Co Ltd, Shanghai 200080, Peoples R China 10.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Zhuang, Youwen,Wang, Yue,He, Bingqing,et al. Molecular recognition of morphine and fentanyl by the human mu-opioid receptor[J]. CELL,2022,185(23).
APA	Zhuang, Youwen.,Wang, Yue.,He, Bingqing.,He, Xinheng.,Zhou, X. Edward.,...&Xu, H. Eric.(2022).Molecular recognition of morphine and fentanyl by the human mu-opioid receptor.CELL,185(23).
MLA	Zhuang, Youwen,et al."Molecular recognition of morphine and fentanyl by the human mu-opioid receptor".CELL 185.23(2022).