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; Yi Jiang

doi:10.1038/s41586-024-07437-6

Dimerization and antidepressant recognition at noradrenaline transporter

Nature. 2024 May 15. doi: 10.1038/s41586-024-07437-6. Online ahead of print.

Authors

Heng Zhang^#¹, Yu-Ling Yin^#², Antao Dai^#^{3

4}, Tianwei Zhang^{2

5}, Chao Zhang^{4

6}, Canrong Wu¹, Wen Hu^{1

7}, Xinheng He^{1

8}, Benxun Pan², Sanshan Jin², Qingning Yuan^{1

7}, Ming-Wei Wang^{9

10

11}, Dehua Yang^{12

13

14}, H Eric Xu^{15

16

17}, Yi Jiang^{18

19}

Affiliations

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
² Lingang Laboratory, Shanghai, China.
³ State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁴ National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁵ School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
⁶ School of Pharmacy, Fudan University, Shanghai, China.
⁷ Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁸ University of Chinese Academy of Sciences, Beijing, China.
⁹ Research Center for Deepsea Bioresources, Sanya, China.
¹⁰ Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
¹¹ School of Pharmacy, Hainan Medical University, Haikou, China.
¹² State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. dhyang@simm.ac.cn.
¹³ National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. dhyang@simm.ac.cn.
¹⁴ University of Chinese Academy of Sciences, Beijing, China. dhyang@simm.ac.cn.
¹⁵ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. eric.xu@simm.ac.cn.
¹⁶ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. eric.xu@simm.ac.cn.
¹⁷ Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. eric.xu@simm.ac.cn.
¹⁸ Lingang Laboratory, Shanghai, China. yjiang@lglab.ac.cn.
¹⁹ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. yjiang@lglab.ac.cn.

^# Contributed equally.

PMID: 38750358
DOI: 10.1038/s41586-024-07437-6

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.