多巴胺转运体
多巴胺
运输机
化学
神经科学
药理学
生物
多巴胺能
生物化学
基因
作者
Dushyant Kumar Srivastava,Vikas Navratna,Dilip K. Tosh,Audrey Chinn,Md Fulbabu Sk,Emad Tajkhorshid,Kenneth A. Jacobson,Eric Gouaux
出处
期刊:Nature
[Springer Nature]
日期:2024-08-07
标识
DOI:10.1038/s41586-024-07739-9
摘要
Abstract The neurotransmitter dopamine has central roles in mood, appetite, arousal and movement 1 . Despite its importance in brain physiology and function, and as a target for illicit and therapeutic drugs, the human dopamine transporter (hDAT) and mechanisms by which it is inhibited by small molecules and Zn 2+ are without a high-resolution structural context. Here we determine the structure of hDAT in a tripartite complex with the competitive inhibitor and cocaine analogue, (–)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane 2 (β-CFT), the non-competitive inhibitor MRS7292 3 and Zn 2 + (ref. 4 ). We show how β-CFT occupies the central site, approximately halfway across the membrane, stabilizing the transporter in an outward-open conformation. MRS7292 binds to a structurally uncharacterized allosteric site, adjacent to the extracellular vestibule, sequestered underneath the extracellular loop 4 (EL4) and adjacent to transmembrane helix 1b (TM1b), acting as a wedge, precluding movement of TM1b and closure of the extracellular gate. A Zn 2+ ion further stabilizes the outward-facing conformation by coupling EL4 to EL2, TM7 and TM8, thus providing specific insights into how Zn 2+ restrains the movement of EL4 relative to EL2 and inhibits transport activity.
科研通智能强力驱动
Strongly Powered by AbleSci AI