2. Academic Validation
  3. Transport and inhibition mechanisms of the human noradrenaline transporter

Transport and inhibition mechanisms of the human noradrenaline transporter

  • Nature. 2024 Aug;632(8026):930-937. doi: 10.1038/s41586-024-07638-z.
Tuo Hu # 1 2 3,  Zhuoya Yu # 1 2 3,  Jun Zhao # 4,  Yufei Meng 1 2 3,  Kristine Salomon 5,  Qinru Bai 1 2 3,  Yiqing Wei 1 2 3,  Jinghui Zhang 6,  Shujing Xu 7,  Qiuyun Dai 7,  Rilei Yu 6,  Bei Yang 1,  Claus J Loland 8,  Yan Zhao 9 10
Affiliations

Affiliations

  • 1 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 2 State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 3 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
  • 4 Peking University Institute of Advanced Agricultural Sciences, Shandong Laboratory of Advanced Agricultural Sciences at Weifang, Weifang, China.
  • 5 Laboratory for Membrane Protein Dynamics, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 6 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
  • 7 Beijing Institute of Biotechnology, Beijing, China.
  • 8 Laboratory for Membrane Protein Dynamics, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. cllo@sund.ku.dk.
  • 9 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. zhaoy@ibp.ac.cn.
  • 10 Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China. zhaoy@ibp.ac.cn.
  • # Contributed equally.
PMID: 39085602 DOI: 10.1038/s41586-024-07638-z
Abstract

The noradrenaline transporter (also known as norepinephrine transporter) (NET) has a critical role in terminating noradrenergic transmission by utilizing sodium and chloride gradients to drive the reuptake of noradrenaline (also known as norepinephrine) into presynaptic neurons1-3. It is a pharmacological target for various antidepressants and analgesic drugs4,5. Despite decades of research, its structure and the molecular mechanisms underpinning noradrenaline transport, coupling to ion gradients and non-competitive inhibition remain unknown. Here we present high-resolution complex structures of NET in two fundamental conformations: in the apo state, and bound to the substrate noradrenaline, an analogue of the χ-conotoxin MrlA (χ-MrlAEM), bupropion or ziprasidone. The noradrenaline-bound structure clearly demonstrates the binding modes of noradrenaline. The coordination of Na+ and Cl- undergoes notable alterations during conformational changes. Analysis of the structure of NET bound to χ-MrlAEM provides insight into how conotoxin binds allosterically and inhibits NET. Additionally, bupropion and ziprasidone stabilize NET in its inward-facing state, but they have distinct binding pockets. These structures define the mechanisms governing neurotransmitter transport and non-competitive inhibition in NET, providing a blueprint for future drug design.

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