Substrate binding and inhibition mechanism of norepinephrine transporter

• 成果类型: Article
• 署名作者: Ji, Wenming; Miao, Anran; Liang, Kai; Liu, Jiameng; Qi, Yuhan; Zhou, Yue; Duan, Xinli; Sun, Jixue; Lai, Lipeng; Wu, Jing-Xiang
• 署名单位: Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5784
• DOI: 10.1038/s41586-024-07810-5
• 发表日期: 2024-09-12
• 页码: 473-479
• 关键词: c-terminus; cryo-em; neurotransmitter; serotonin; metaiodobenzylguanidine; CHALLENGES; STABILITY; DISCOVERY; DYNAMICS; antibody

摘要

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. Structures of human NET in the apo state and bound to meta-iodobenzylguanidine and radafaxine provide insights into the mechanism of substrate recognition and orthosteric inhibition of hNET.