Transport and inhibition mechanisms of the human noradrenaline transporter

• 成果类型: Article
• 署名作者: Hu, Tuo; Yu, Zhuoya; Zhao, Jun; Meng, Yufei; Salomon, Kristine; Bai, Qinru; Wei, Yiqing; Zhang, Jinghui; Xu, Shujing; Dai, Qiuyun; Yu, Rilei; Yang, Bei; Loland, Claus J.; Zhao, Yan
• 署名单位: Chinese Academy of Sciences; Institute of Biophysics, CAS; Chinese Academy of Sciences; Institute of Biophysics, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Peking University; University of Copenhagen; Ocean University of China; Capital Medical University; Capital Medical University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5142
• DOI: 10.1038/s41586-024-07638-z
• 发表日期: 2024-08-22
• 页码: 930-+
• 关键词: norepinephrine transporter; dopamine transporter; expression; neurotransmitter; TRAFFICKING; RECOGNITION; mutations; STABILITY; SYSTEM

摘要

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 neurons(1-3). It is a pharmacological target for various antidepressants and analgesic drugs(4,5). 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 chi-conotoxin MrlA (chi-MrlA(EM)), 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 chi-MrlA(EM) 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.