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Unveiling conformation-selective regulation of the norepinephrine transporter

文献类型：期刊论文

作者Zhang, Heng2; Zhang, Tianwei1,3; Wang, Dingyan3; Dai, Antao4,5; Mao, Jianhang1,3; Chen, Qihui3; Du, Tianyuan6; Lu, Xue3; Hao, Yongxin7; Zhang, Chao5,8
刊名CELL
出版日期2025-11-26
卷号188期号:24页码:27
ISSN号0092-8674
DOI10.1016/j.cell.2025.10.002
英文摘要The norepinephrine transporter (NET) plays a crucial role in synaptic neurotransmission and is implicated in major depression and attention-deficit/hyperactivity disorders, yet our understanding of its allosteric, conformation-selective regulation-crucial for developing targeted therapeutics-remains limited. Through cryoelectron microscopy analysis of NET complexes with levomilnacipran, vanoxerine, and vilazodone, we identify a previously undefined allosteric site within NET's inner vestibule that enables conformation-selective regulation. This discovery introduces a "valve model," in which specific residues partition the cytoplasmic cavity into distinct chambers, determining inhibitor binding specificity. Leveraging this structural insight through virtual screening, we identify a set of inhibitors with potent NET inhibitory activity and demonstrate their antidepressant effects. Moreover, our structural identification of inhibitor occupancy at this conformation-selective site defines a mechanistic framework for targeted therapeutic intervention. These findings advance our understanding of NET allosteric modulation, providing a structure-guided framework for developing next-generation antidepressants targeting the inward-open conformation of NET for the treatment of neuropsychiatric disorders.
WOS关键词MAJOR DEPRESSIVE DISORDER ; X-RAY STRUCTURES ; DOPAMINE TRANSPORTER ; SEROTONIN ; LEVOMILNACIPRAN ; RECOGNITION ; MECHANISMS ; OCCUPANCY
资助项目National Natural Science Foundation[32171187] ; National Natural Science Foundation[82121005] ; National Natural Science Foundation[32130022] ; National Natural Science Foundation[82273985] ; Lingang Laboratory[LG-GG-202204-01] ; Program of Shanghai Academic/Technology Research Leader[22XD1425200] ; Program of Shanghai Academic/Technology Research Leader[23XD1400900] ; Shanghai Oriental Talents Program ; CAS Strategic Priority Research Program[XDB37030103] ; CAS Strategic Priority Research Program[XDB1060402] ; National Key Basic Research Program of China[2023YFA1800804] ; Sanya Science and Technology Innovation Special Project[2022KJCX77] ; Young Elite Scientists Sponsorship Program by CAST[2024-2026QNRC001] ; China Postdoctoral Science Foundation[2023M731487] ; China Postdoctoral Science Foundation[2024T170373] ; Shanghai Sailing Program[2023018] ; Shanghai Sailing Program[2022232] ; Shanghai Post-doctoral Excellence Program ; [23YF1460700] ; [22YF1461200]
WOS研究方向Biochemistry & Molecular Biology ; Cell Biology
语种英语
WOS记录号WOS:001632367300012
出版者CELL PRESS
源URL[http://119.78.100.183/handle/2S10ELR8/322572]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Wang, Zhen; Yang, Dehua; Xu, H. Eric; Jiang, Yi
作者单位1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Lingang Lab, Shanghai 201100, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
5.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
6.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
7.Univ Sci & Technol China, Div Life Sci & Med, Hefei 230026, Anhui, Peoples R China
8.Fudan Univ Shanghai, Sch Pharm, Shanghai 201203, Peoples R China
9.Chinese Acad Sci, Shanghai Adv Electron Microscope Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
10.Shanghai Jiao Tong Univ, Natl Res Ctr Translat Med Shanghai, Res Ctr Med Struct Biol, State Key Lab Med Genom,Sch Med,Ruijin Hosp, Shanghai 200025, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Heng,Zhang, Tianwei,Wang, Dingyan,et al. Unveiling conformation-selective regulation of the norepinephrine transporter[J]. CELL,2025,188(24):27.
APA Zhang, Heng.,Zhang, Tianwei.,Wang, Dingyan.,Dai, Antao.,Mao, Jianhang.,...&Jiang, Yi.(2025).Unveiling conformation-selective regulation of the norepinephrine transporter.CELL,188(24),27.
MLA Zhang, Heng,et al."Unveiling conformation-selective regulation of the norepinephrine transporter".CELL 188.24(2025):27.

入库方式： OAI收割

来源：上海药物研究所

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