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Dimerization and antidepressant recognition at noradrenaline transporter

文献类型：期刊论文

作者Zhang, Heng11; Yin, Yu-Ling10; Dai, Antao8,9; Zhang, Tianwei7,10; Zhang, Chao6,8; Wu, Canrong11; Hu, Wen5,11; He, Xinheng4,11; Pan, Benxun10; Jin, Sanshan10
刊名NATURE
出版日期2024-05-15
页码24
ISSN号0028-0836
DOI10.1038/s41586-024-07437-6
通讯作者Yang, Dehua(dhyang@simm.ac.cn) ; Xu, H. Eric(eric.xu@simm.ac.cn) ; Jiang, Yi(yjiang@lglab.ac.cn)
英文摘要The noradrenaline transporter has a pivotal role in regulating neurotransmitter balance and is crucial for normal physiology and neurobiology1. Dysfunction of noradrenaline transporter has been implicated in numerous neuropsychiatric diseases, including depression and attention deficit hyperactivity disorder2. Here we report cryo-electron microscopy structures of noradrenaline transporter in apo and substrate-bound forms, and as complexes with six antidepressants. The structures reveal a noradrenaline transporter dimer interface that is mediated predominantly by cholesterol and lipid molecules. The substrate noradrenaline binds deep in the central binding pocket, and its amine group interacts with a conserved aspartate residue. Our structures also provide insight into antidepressant recognition and monoamine transporter selectivity. Together, these findings advance our understanding of noradrenaline transporter regulation and inhibition, and provide templates for designing improved antidepressants to treat neuropsychiatric disorders. Cryo-electron microscopy structures of the noradrenaline transporter in the apo state, bound to noradrenaline and bound to various antidepressants shed light on the substrate transport, molecular recognition and dimeric architecture of this protein.
WOS关键词TRIPLE REUPTAKE INHIBITORS ; X-RAY STRUCTURES ; DOPAMINE TRANSPORTER ; NOREPINEPHRINE TRANSPORTER ; HUMAN SEROTONIN ; CRYO-EM ; DIVERSE ANTIDEPRESSANTS ; MONOAMINE TRANSPORTERS ; STRUCTURAL BASIS ; NEUROTRANSMITTER
资助项目ShanghaiTech University ; Lingang Laboratory[LG-GG-202204-01] ; National Natural Science Foundation[32171187] ; National Natural Science Foundation[82121005] ; National Natural Science Foundation[32130022] ; National Natural Science Foundation[82273985] ; CAS Strategic Priority Research Program[XDB37030103] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; National Key Basic Research Program of China[2023YFA1800804] ; Shanghai Municipality Science and Technology Development Fund[21JC1401600] ; Program of Shanghai Academic/Technology Research Leader[23XD1400900] ; Hainan Provincial Major Science and Technology Project[ZDKJ2021028] ; China Postdoctoral Science Foundation[2023M731487] ; Shanghai Post-doctoral Excellence Program[2023018] ; Shanghai Post-doctoral Excellence Program[2022232] ; Shanghai Sailing Program[23YF1460700] ; Shanghai Sailing Program[22YF1461200]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001262383500005
出版者NATURE PORTFOLIO
源URL[http://119.78.100.183/handle/2S10ELR8/312110]  
专题新药研究国家重点实验室
通讯作者Yang, Dehua; Xu, H. Eric; Jiang, Yi
作者单位1.Hainan Med Univ, Sch Pharm, Haikou, Peoples R China
2.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai, Peoples R China
3.Res Ctr Deepsea Bioresources, Sanya, Peoples R China
4.Univ Chinese Acad Sci, Beijing, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai Adv Electron Microscope Ctr, Shanghai, Peoples R China
6.Fudan Univ, Sch Pharm, Shanghai, Peoples R China
7.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
8.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai, Peoples R China
9.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai, Peoples R China
10.Lingang Lab, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Heng,Yin, Yu-Ling,Dai, Antao,et al. Dimerization and antidepressant recognition at noradrenaline transporter[J]. NATURE,2024:24.
APA Zhang, Heng.,Yin, Yu-Ling.,Dai, Antao.,Zhang, Tianwei.,Zhang, Chao.,...&Jiang, Yi.(2024).Dimerization and antidepressant recognition at noradrenaline transporter.NATURE,24.
MLA Zhang, Heng,et al."Dimerization and antidepressant recognition at noradrenaline transporter".NATURE (2024):24.

入库方式： OAI收割

来源：上海药物研究所

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