上海科技大学蒋轶等研究人员合作揭示去甲肾上腺素转运体的二聚化和抗抑郁识别。该项研究成果于2024年5月15日在线发表在《自然》杂志上。

研究人员报告了去甲肾上腺素转运体的冷冻电镜结构，包括与底物结合的形式，以及与六种抗抑郁药物的复合物。这些结构揭示了主要由胆固醇和脂质分子介导的去甲肾上腺素转运体二聚体界面。底物去甲肾上腺素结合在中央结合袋的深处，其胺基与一个保守的天冬氨酸残基相互作用。这些结构还为抗抑郁药物的识别和单胺转运体的选择性提供了见解。

这些发现共同推进了人们对去甲肾上腺素转运体调节和抑制的理解，并为设计治疗神经精神疾病的改良抗抑郁药提供了模板。

研究人员表示，去甲肾上腺素转运体在调节神经递质平衡方面起着关键作用，对正常生理和神经生物学至关重要。去甲肾上腺素转运体的功能障碍与多种神经精神疾病有关，包括抑郁症和注意缺陷多动障碍。

附：英文原文

Title: Dimerization and antidepressant recognition at noradrenaline transporter

Author: Zhang, Heng, Yin, Yu-Ling, Dai, Antao, Zhang, Tianwei, Zhang, Chao, Wu, Canrong, Hu, Wen, He, Xinheng, Pan, Benxun, Jin, Sanshan, Yuan, Qingning, Wang, Ming-Wei, Yang, Dehua, Xu, H. Eric, Jiang, Yi

Issue&Volume: 2024-05-15

Abstract: The noradrenaline transporter has a pivotal role in regulating neurotransmitter balance and is crucial for normal physiology and neurobiology1. Dysfunction of noradrenaline transporter has been implicated in numerous neuropsychiatric diseases, including depression and attention deficit hyperactivity disorder2. Here we report cryo-electron microscopy structures of noradrenaline transporter in apo and substrate-bound forms, and as complexes with six antidepressants. The structures reveal a noradrenaline transporter dimer interface that is mediated predominantly by cholesterol and lipid molecules. The substrate noradrenaline binds deep in the central binding pocket, and its amine group interacts with a conserved aspartate residue. Our structures also provide insight into antidepressant recognition and monoamine transporter selectivity. Together, these findings advance our understanding of noradrenaline transporter regulation and inhibition, and provide templates for designing improved antidepressants to treat neuropsychiatric disorders.

DOI: 10.1038/s41586-024-07437-6

Source: https://www.nature.com/articles/s41586-024-07437-6