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Transport and inhibition mechanisms of the human noradrenaline transporter

Author

Listed:
  • Tuo Hu

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Zhuoya Yu

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jun Zhao

    (Shandong Laboratory of Advanced Agricultural Sciences at Weifang)

  • Yufei Meng

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Kristine Salomon

    (University of Copenhagen)

  • Qinru Bai

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yiqing Wei

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jinghui Zhang

    (Ocean University of China)

  • Shujing Xu

    (Beijing Institute of Biotechnology)

  • Qiuyun Dai

    (Beijing Institute of Biotechnology)

  • Rilei Yu

    (Ocean University of China)

  • Bei Yang

    (Chinese Academy of Sciences)

  • Claus J. Loland

    (University of Copenhagen)

  • Yan Zhao

    (Chinese Academy of Sciences
    Capital Medical University)

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.

Suggested Citation

  • Tuo Hu & Zhuoya Yu & Jun Zhao & Yufei Meng & Kristine Salomon & Qinru Bai & Yiqing Wei & Jinghui Zhang & Shujing Xu & Qiuyun Dai & Rilei Yu & Bei Yang & Claus J. Loland & Yan Zhao, 2024. "Transport and inhibition mechanisms of the human noradrenaline transporter," Nature, Nature, vol. 632(8026), pages 930-937, August.
  • Handle: RePEc:nat:nature:v:632:y:2024:i:8026:d:10.1038_s41586-024-07638-z
    DOI: 10.1038/s41586-024-07638-z
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    Cited by:

    1. Andreas Nygaard & Linda G. Zachariassen & Kathrine S. Larsen & Anders S. Kristensen & Claus J. Loland, 2024. "Fluorescent non-canonical amino acid provides insight into the human serotonin transporter," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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