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Title | Cryo-EM structure of the dopamine transporter with a novel atypical non-competitive inhibitor bound to the orthosteric site. |
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Journal, issue, pages | J Neurochem, Year 2024 |
Publish date | Jul 15, 2024 |
![]() | 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 / ![]() ![]() |
PubMed 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. ...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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Methods | EM (single particle) |
Resolution | 3.0 - 3.2 Å |
Structure data | EMDB-19978, PDB-9euo: EMDB-19979, PDB-9eup: |
Chemicals | ![]() PDB-1h8f: ![]() ChemComp-Y01: ![]() ChemComp-144: ![]() ChemComp-CLR: ![]() ChemComp-NA: ![]() ChemComp-CL: |
Source |
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![]() | MEMBRANE PROTEIN / SLC6A3 / Dopamine transporter / atypical inhibitors / neurotransmitter sodium symporters |