Structure of the human dopamine transporter in complex with cocaine

• 成果类型: Article
• 署名作者: Nielsen, Jeppe C.; Salomon, Kristine; Kalenderoglou, Iris E.; Bargmeyer, Sarah; Pape, Tillmann; Shahsavar, Azadeh; Loland, Claus J.
• 署名单位: University of Copenhagen; Novo Nordisk Foundation; University of Copenhagen; University of Copenhagen; University of Copenhagen
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5672
• DOI: 10.1038/s41586-024-07804-3
• 发表日期: 2024-08-15
• 页码: 678-+
• 关键词: force-field; c-terminus; serotonin; neurotransmitter; binding; conformation; amphetamine; RECOGNITION; validation; permeation

摘要

The dopamine transporter (DAT) is crucial for regulating dopamine signalling and is the prime mediator for the rewarding and addictive effects of cocaine(1). As part of the neurotransmitter sodium symporter family, DAT uses the Na+ gradient across cell membranes to transport dopamine against its chemical gradient(2). The transport mechanism involves both intra- and extracellular gates that control substrate access to a central site. However, the molecular intricacies of this process and the inhibitory mechanism of cocaine have remained unclear. Here, we present the molecular structure of human DAT in complex with cocaine at a resolution of 2.66 angstrom. Our findings reveal that DAT adopts the expected LeuT-fold, posing in an outward-open conformation with cocaine bound at the central (S1) site. Notably, while an Na+ occupies the second Na+ site (Na2), the Na1 site seems to be vacant, with the side chain of Asn82 occupying the presumed Na+ space. This structural insight elucidates the mechanism for the cocaine inhibition of human DAT and deepens our understanding of neurotransmitter transport. By shedding light on the molecular underpinnings of how cocaine acts, our study lays a foundation for the development of targeted medications to combat addiction.