ArticleJournal of neurochemistry2024
Cryo-EM structure of the dopamine transporter with a novel atypical non-competitive inhibitor bound to the orthosteric site.
Article in Journal of neurochemistry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Unraveling competitive protein interactions: A critical step toward improved production and therapeutics.Journal of advanced research · 2026Review
- A reversible allosteric inhibitor of GlyT2 for neuropathic pain without on-target side effects.Nature communications · 2026Article
- Structural basis for selective inhibition of human GABA transporter GAT3.Nature communications · 2026Article
- Biological Breakthroughs and Drug Discovery Revolution via Cryo-Electron Microscopy of Membrane Proteins.Membranes · 2025Review
- A reversible allosteric inhibitor of GlyT2 alleviates neuropathic pain without on-target side effects.bioRxiv : the preprint server for biology · 2025Article
- Novel Ways of Targeting the Dopamine Transporter.Advances in neurobiology · 2025Review
- Orthoflaviviral Inhibitors in Clinical Trials, Preclinical In Vivo Efficacy Targeting NS2B-NS3 and Cellular Antiviral Activity via Competitive Protease Inhibition.Molecules (Basel, Switzerland) · 2024Review
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Authors and funding
13 authors.
Funding
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.
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