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

文献类型：期刊论文

作者Zhuang, Youwen1; Wang, Yue1,2; He, Bingqing2,3,4; He, Xinheng1,2; Zhou, X. Edward5; Guo, Shimeng2,3,6; Rao, Qidi4; Yang, Jiaqi1; Liu, Jinyu6; Zhou, Qingtong7
刊名CELL
出版日期2022-11-10
卷号185期号:23页码:4361-+
ISSN号0092-8674
DOI10.1016/j.cell.2022.09.041
通讯作者Zhuang, Youwen(zhuangyouwen@simm.ac.cn) ; Wang, Ming-Wei(mwwang@simm.ac.cn) ; Xie, Xin(xxie@simm.ac.cn) ; Xu, H. Eric(eric.xu@simm.ac.cn)
英文摘要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.
WOS关键词PROTEIN-BIASED LIGAND ; STRUCTURAL INSIGHTS ; CRYSTAL-STRUCTURE ; MICE LACKING ; ANALGESICS ; TRV130 ; OLICERIDINE ; DISCOVERY
资助项目Ministry of Science and Technology (China)[2018YFA0507000] ; Ministry of Science and Technology (China)[2018YFA0507002] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[32130022] ; National Natural Science Foundation of China[81730099] ; National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[82073904] ; National Natural Science Foundation of China[32171187] ; National Natural Science Foundation of China[81773792] ; National Natural Science Foundation of China[81973373] ; National Natural Science Foundation of China[21704064] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; CAS Strategic Priority Research Program[XDB37030103] ; Shanghai Municipal Science and Technology Major Project ; National Science &Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09735-001] ; National Science &Technology Major Project of China-Key New Drug Creation and Manufacturing Program[018ZX09711002-002-005] ; Special Research Assistant Project of Chinese Academy of Sciences
WOS研究方向Biochemistry & Molecular Biology ; Cell Biology
语种英语
WOS记录号WOS:000900775500003
出版者CELL PRESS
源URL[http://119.78.100.183/handle/2S10ELR8/304055]  
专题新药研究国家重点实验室
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
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):4361-+.
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),4361-+.
MLA Zhuang, Youwen,et al."Molecular recognition of morphine and fentanyl by the human mu-opioid receptor".CELL 185.23(2022):4361-+.

入库方式： OAI收割

来源：上海药物研究所

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