Structure of the human dopamine transporter in complex with cocaine

Jeppe C. Nielsen, Kristine Salomon, Iris E. Kalenderoglou, Sarah Bargmeyer, Tillmann Pape, Azadeh Shahsavar and Claus J. Loland ()
Additional contact information
Jeppe C. Nielsen: University of Copenhagen
Kristine Salomon: University of Copenhagen
Iris E. Kalenderoglou: University of Copenhagen
Sarah Bargmeyer: University of Copenhagen
Tillmann Pape: University of Copenhagen
Azadeh Shahsavar: University of Copenhagen
Claus J. Loland: University of Copenhagen

Nature, 2024, vol. 632, issue 8025, 678-685

Abstract: Abstract The dopamine transporter (DAT) is crucial for regulating dopamine signalling and is the prime mediator for the rewarding and addictive effects of cocaine1. As part of the neurotransmitter sodium symporter family, DAT uses the Na+ gradient across cell membranes to transport dopamine against its chemical gradient2. 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 Å. 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.

Date: 2024
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41586-024-07804-3 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:632:y:2024:i:8025:d:10.1038_s41586-024-07804-3

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-024-07804-3

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().