Dopamine reuptake and inhibitory mechanisms in human dopamine transporter

Yue Li, Xianping Wang, Yufei Meng, Tuo Hu, Jun Zhao, Renjie Li, Qinru Bai, Pu Yuan, Jun Han, Kun Hao, Yiqing Wei, Yunlong Qiu, Na Li and Yan Zhao ()
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Yue Li: Chinese Academy of Sciences
Xianping Wang: Chinese Academy of Sciences
Yufei Meng: Chinese Academy of Sciences
Tuo Hu: Chinese Academy of Sciences
Jun Zhao: Shandong Laboratory of Advanced Agricultural Sciences at Weifang
Renjie Li: Chinese Academy of Sciences
Qinru Bai: Chinese Academy of Sciences
Pu Yuan: Chinese Academy of Sciences
Jun Han: Chinese Academy of Sciences
Kun Hao: Chinese Academy of Sciences
Yiqing Wei: Chinese Academy of Sciences
Yunlong Qiu: Chinese Academy of Sciences
Na Li: Capital Medical University
Yan Zhao: Chinese Academy of Sciences

Nature, 2024, vol. 632, issue 8025, 686-694

Abstract: Abstract The dopamine transporter has a crucial role in regulation of dopaminergic neurotransmission by uptake of dopamine into neurons and contributes to the abuse potential of psychomotor stimulants1–3. Despite decades of study, the structure, substrate binding, conformational transitions and drug-binding poses of human dopamine transporter remain unknown. Here we report structures of the human dopamine transporter in its apo state, and in complex with the substrate dopamine, the attention deficit hyperactivity disorder drug methylphenidate, and the dopamine-uptake inhibitors GBR12909 and benztropine. The dopamine-bound structure in the occluded state precisely illustrates the binding position of dopamine and associated ions. The structures bound to drugs are captured in outward-facing or inward-facing states, illuminating distinct binding modes and conformational transitions during substrate transport. Unlike the outward-facing state, which is stabilized by cocaine, GBR12909 and benztropine stabilize the dopamine transporter in the inward-facing state, revealing previously unseen drug-binding poses and providing insights into how they counteract the effects of cocaine. This study establishes a framework for understanding the functioning of the human dopamine transporter and developing therapeutic interventions for dopamine transporter-related disorders and cocaine addiction.

Date: 2024
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DOI: 10.1038/s41586-024-07796-0

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