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
  • 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. [email protected].
  • 9. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. [email protected].
  • 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. [email protected].
  • # 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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