Transport and inhibition mechanisms of the human noradrenaline transporter

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 () and Yan Zhao ()
Additional contact information
Tuo Hu: Chinese Academy of Sciences
Zhuoya Yu: Chinese Academy of Sciences
Jun Zhao: Shandong Laboratory of Advanced Agricultural Sciences at Weifang
Yufei Meng: Chinese Academy of Sciences
Kristine Salomon: University of Copenhagen
Qinru Bai: Chinese Academy of Sciences
Yiqing Wei: 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

Nature, 2024, vol. 632, issue 8026, 930-937

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07638-z

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