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TitleCryo-EM structure of the dopamine transporter with a novel atypical non-competitive inhibitor bound to the orthosteric site.
Journal, issue, pagesJ Neurochem, Vol. 168, Issue 9, Page 2043-2055, Year 2024
Publish dateJul 15, 2024
AuthorsClara 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 AbstractThe 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.
External linksJ Neurochem / PubMed:39010681 / PubMed Central
MethodsEM (single particle)
Resolution3.0 - 3.2 Å
Structure data

19978

9euo

EMDB-19978, PDB-9euo:
Outward-open structure of Drosophila dopamine transporter bound to an atypical non-competitive inhibitor
Method: EM (single particle) / Resolution: 3.2 Å

19979

9eup

EMDB-19979, PDB-9eup:
Inhibitor-free outward-open structure of Drosophila dopamine transporter
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

PDB-1h8f:
Glycogen Synthase Kinase 3 beta.

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-144:
TRIS-HYDROXYMETHYL-METHYL-AMMONIUM

ChemComp-CLR:
CHOLESTEROL

ChemComp-NA:
Unknown entry

ChemComp-CL:
Unknown entry

Source
  • drosophila melanogaster (fruit fly)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / SLC6A3 / Dopamine transporter / atypical inhibitors / neurotransmitter sodium symporters

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