Substrate binding and inhibition mechanism of norepinephrine transporter

Wenming Ji, Anran Miao, Kai Liang, Jiameng Liu, Yuhan Qi, Yue Zhou, Xinli Duan, Jixue Sun, Lipeng Lai and Jing-Xiang Wu ()
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Wenming Ji: Chinese Academy of Medical Sciences & Peking Union Medical College
Anran Miao: Chinese Academy of Medical Sciences & Peking Union Medical College
Kai Liang: Chinese Academy of Medical Sciences & Peking Union Medical College
Jiameng Liu: Chinese Academy of Medical Sciences & Peking Union Medical College
Yuhan Qi: Chinese Academy of Medical Sciences & Peking Union Medical College
Yue Zhou: Chinese Academy of Medical Sciences & Peking Union Medical College
Xinli Duan: Beijing Jingtai Technology
Jixue Sun: Beijing Jingtai Technology
Lipeng Lai: Beijing Jingtai Technology
Jing-Xiang Wu: Chinese Academy of Medical Sciences & Peking Union Medical College

Nature, 2024, vol. 633, issue 8029, 473-479

Abstract: Abstract Norepinephrine transporter (NET; encoded by SLC6A2) reuptakes the majority of the released noradrenaline back to the presynaptic terminals, thereby affecting the synaptic noradrenaline level1. Genetic mutations and dysregulation of NET are associated with a spectrum of neurological conditions in humans, making NET an important therapeutic target1. However, the structure and mechanism of NET remain unclear. Here we provide cryogenic electron microscopy structures of the human NET (hNET) in three functional states—the apo state, and in states bound to the substrate meta-iodobenzylguanidine (MIBG) or the orthosteric inhibitor radafaxine. These structures were captured in an inward-facing conformation, with a tightly sealed extracellular gate and an open intracellular gate. The substrate MIBG binds at the centre of hNET. Radafaxine also occupies the substrate-binding site and might block the structural transition of hNET for inhibition. These structures provide insights into the mechanism of substrate recognition and orthosteric inhibition of hNET.

Date: 2024
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DOI: 10.1038/s41586-024-07810-5

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