2. Academic Validation
  3. Unveiling conformation-selective regulation of the norepinephrine transporter

Unveiling conformation-selective regulation of the norepinephrine transporter

  • Cell. 2025 Oct 24:S0092-8674(25)01131-6. doi: 10.1016/j.cell.2025.10.002.
Heng Zhang 1,  Tianwei Zhang 2,  Dingyan Wang 3,  Antao Dai 4,  Jianhang Mao 2,  Qihui Chen 3,  Tianyuan Du 5,  Xue Lu 3,  Yongxin Hao 6,  Chao Zhang 7,  Yu-Ling Yin 3,  Wen Hu 8,  Benxun Pan 3,  Sanshan Jin 2,  Mengting Jiang 2,  Yuan Si 3,  Qingning Yuan 9,  Ming-Wei Wang 10,  Mingyue Zheng 11,  Zhen Wang 12,  Dehua Yang 13,  H Eric Xu 14,  Yi Jiang 15
Affiliations

Affiliations

  • 1 The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 Lingang Laboratory, Shanghai 201100, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 3 Lingang Laboratory, Shanghai 201100, China.
  • 4 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 6 Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230026, Anhui, China.
  • 7 The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmacy, Fudan University Shanghai, Shanghai 201203, China.
  • 8 The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 9 Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 10 Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Research Center for Deepsea Bioresources, Sanya 572025, Hainan, China.
  • 11 The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 12 Lingang Laboratory, Shanghai 201100, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: wangzhen@lglab.ac.cn.
  • 13 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; 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 210023, China. Electronic address: dhyang@simm.ac.cn.
  • 14 The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: eric.xu@simm.ac.cn.
  • 15 Lingang Laboratory, Shanghai 201100, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: yjiang@lglab.ac.cn.
PMID: 41138730 DOI: 10.1016/j.cell.2025.10.002
Abstract

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 cryo-electron 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.

Keywords

allosteric site; conformational selectivity; inward-open; levomilnacipran; norepinephrine transporter; valve model; vanoxerine; vilazodone.

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