Dimerization and antidepressant recognition at noradrenaline transporter

• 成果类型: Article
• 署名作者: 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
• 署名单位: Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; Lingang Laboratory; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; ShanghaiTech University; Fudan University; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Fudan University; Hainan Medical University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3721
• DOI: 10.1038/s41586-024-07437-6
• 发表日期: 2024-06-06
• 关键词: triple reuptake inhibitors; x-ray structures; dopamine transporter; norepinephrine transporter; human serotonin; cryo-em; diverse antidepressants; monoamine transporters; structural basis; neurotransmitter

摘要

The noradrenaline transporter has a pivotal role in regulating neurotransmitter balance and is crucial for normal physiology and neurobiology(1). Dysfunction of noradrenaline transporter has been implicated in numerous neuropsychiatric diseases, including depression and attention deficit hyperactivity disorder(2). 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.