Cryo-EM structure of the dopamine transporter with a novel atypical non-competitive inhibitor bound to the orthosteric site

Clara Nautrup Pedersen, Fuyu Yang, Samantha Ita, Yibin Xu, Ravikumar Akunuri, Sofia Trampari, Caroline Marie Teresa Neumann, Lasse Messell Desdorf, Birgit Schiøtt, Joseph M Salvino, Ole Valente Mortensen*, Poul Nissen*, Azadeh Shahsavar*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

1 Citation (Scopus)

Abstract

The regulation of dopamine (DA) removal from the synaptic cleft is a crucial process in neurotransmission and is facilitated by the sodium- and chloride-coupled dopamine transporter DAT. Psychostimulant drugs, cocaine, and amphetamine, both block the uptake of DA, while amphetamine also triggers the release of DA. As a result, they prolong or even amplify neurotransmitter signaling. Atypical inhibitors of DAT lack cocaine-like rewarding effects and offer a promising strategy for the treatment of drug use disorders. Here, we present the 3.2 Å resolution cryo-electron microscopy structure of the Drosophila melanogaster dopamine transporter (dDAT) in complex with the atypical non-competitive inhibitor AC-4-248. The inhibitor partially binds at the central binding site, extending into the extracellular vestibule, and locks the transporter in an outward open conformation. Our findings propose mechanisms for the non-competitive inhibition of DAT and attenuation of cocaine potency by AC-4-248 and provide a basis for the rational design of more efficacious atypical inhibitors. (Figure presented.)

Original languageEnglish
JournalJournal of Neurochemistry
Volume168
Issue9
Pages (from-to)2043-2055
Number of pages13
ISSN0022-3042
DOIs
Publication statusPublished - Sept 2024

Keywords

  • atypical inhibitor
  • cryo-electron microscopy
  • dopamine transporter
  • neurotransmitter transporter

Fingerprint

Dive into the research topics of 'Cryo-EM structure of the dopamine transporter with a novel atypical non-competitive inhibitor bound to the orthosteric site'. Together they form a unique fingerprint.

Cite this