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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