中国科学院生物物理所赵岩团队近期取得重要工作进展。他们研究提出了人多巴胺转运蛋白的多巴胺再摄取及其抑制机制。相关研究成果2024年8月7日在线发表于《自然》杂志上。

据介绍，多巴胺转运体通过将多巴胺摄取到神经元中，在调节多巴胺能神经传递中起着至关重要的作用。尽管经过几十年的研究，人类多巴胺转运蛋白的结构、底物结合、构象转变和药物结合状态仍然未知。

研究人员报告了处于载脂蛋白状态下的人类多巴胺转运蛋白的结构，以及与底物多巴胺、注意缺陷多动障碍药物methylphenidate、多巴胺摄取抑制剂GBR12909和benztropine的复合物。

处于闭塞状态下的多巴胺结合结构精确地说明了多巴胺和相关离子的结合位置。与药物结合的结构以外向或内向的状态被捕获，阐明了底物运输过程中不同的结合模式和构象转变。与可卡因稳定的外向状态不同，GBR12909和benztropine将多巴胺转运蛋白稳定在内向状态，揭示了以前看不见的药物结合姿势，并提供了它们如何抵消可卡因影响的见解。

总之，本研究为理解人类多巴胺转运体的功能和开发多巴胺转运体相关疾病和可卡因成瘾的治疗干预措施建立了一个框架。

附：英文原文

Title: Dopamine reuptake and inhibitory mechanisms in human dopamine transporter

Author: Li, Yue, Wang, Xianping, Meng, Yufei, Hu, Tuo, Zhao, Jun, Li, Renjie, Bai, Qinru, Yuan, Pu, Han, Jun, Hao, Kun, Wei, Yiqing, Qiu, Yunlong, Li, Na, Zhao, Yan

Issue&Volume: 2024-08-07

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 stimulants1,2,3. 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.

DOI: 10.1038/s41586-024-07796-0

Source: https://www.nature.com/articles/s41586-024-07796-0