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.

去甲肾上腺素转运蛋白在调节神经递质平衡方面发挥着关键作用，对于正常生理学和神经生物学至关重要¹。去甲肾上腺素转运蛋白功能障碍与许多神经精神疾病有关，包括抑郁症和注意力缺陷多动障碍²。在这里，我们报道了载脂蛋白和底物结合形式的去甲肾上腺素转运蛋白的冷冻电子显微镜结构，以及与六种抗抑郁药的复合物。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蛋白二聚体界面。底物去甲肾上腺素在中央结合袋深处结合，其胺基与保守的天冬氨酸残基相互作用。我们的结构还提供了抗抑郁药识别和单胺转运蛋白选择性的见解。总之，这些发现增进了我们对去甲肾上腺素转运蛋白调节和抑制的理解，并为设计改进的抗抑郁药物治疗神经精神疾病提供了模板。