Molecular basis of human noradrenaline transporter reuptake and inhibition

Jiaxin Tan, Yuan Xiao, Fang Kong, Xiaochun Zhang, Hanwen Xu, Angqi Zhu, Yiming Liu, Jianlin Lei, Boxue Tian, Yafei Yuan () and Chuangye Yan ()
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Jiaxin Tan: Tsinghua University
Yuan Xiao: Tsinghua University
Fang Kong: Tsinghua University
Xiaochun Zhang: Tsinghua University
Hanwen Xu: Tsinghua University
Angqi Zhu: Tsinghua University
Yiming Liu: Tsinghua University
Jianlin Lei: Tsinghua University
Boxue Tian: Tsinghua University
Yafei Yuan: Tsinghua University
Chuangye Yan: Tsinghua University

Nature, 2024, vol. 632, issue 8026, 921-929

Abstract: Abstract Noradrenaline, also known as norepinephrine, has a wide range of activities and effects on most brain cell types1. Its reuptake from the synaptic cleft heavily relies on the noradrenaline transporter (NET) located in the presynaptic membrane2. Here we report the cryo-electron microscopy (cryo-EM) structures of the human NET in both its apo state and when bound to substrates or antidepressant drugs, with resolutions ranging from 2.5 Å to 3.5 Å. The two substrates, noradrenaline and dopamine, display a similar binding mode within the central substrate binding site (S1) and within a newly identified extracellular allosteric site (S2). Four distinct antidepressants, namely, atomoxetine, desipramine, bupropion and escitalopram, occupy the S1 site to obstruct substrate transport in distinct conformations. Moreover, a potassium ion was observed within sodium-binding site 1 in the structure of the NET bound to desipramine under the KCl condition. Complemented by structural-guided biochemical analyses, our studies reveal the mechanism of substrate recognition, the alternating access of NET, and elucidate the mode of action of the four antidepressants.

Date: 2024
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DOI: 10.1038/s41586-024-07719-z

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