Dimerization and antidepressant recognition at noradrenaline transporter

Heng Zhang, Yu-Ling Yin, Antao Dai, Tianwei Zhang, Chao Zhang, Canrong Wu, Wen Hu, Xinheng He, Benxun Pan, Sanshan Jin, Qingning Yuan, Ming-Wei Wang, Dehua Yang (), H. Eric Xu () and Yi Jiang ()
Additional contact information
Heng Zhang: Chinese Academy of Sciences
Yu-Ling Yin: Lingang Laboratory
Antao Dai: Chinese Academy of Sciences
Tianwei Zhang: Lingang Laboratory
Chao Zhang: Chinese Academy of Sciences
Canrong Wu: Chinese Academy of Sciences
Wen Hu: Chinese Academy of Sciences
Xinheng He: Chinese Academy of Sciences
Benxun Pan: Lingang Laboratory
Sanshan Jin: Lingang Laboratory
Qingning Yuan: Chinese Academy of Sciences
Ming-Wei Wang: Research Center for Deepsea Bioresources
Dehua Yang: Chinese Academy of Sciences
H. Eric Xu: Chinese Academy of Sciences
Yi Jiang: Lingang Laboratory

Nature, 2024, vol. 630, issue 8015, 247-254

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07437-6

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