9EUP

Inhibitor-free outward-open structure of Drosophila dopamine transporter

Summary for 9EUP

• Entry DOI: 10.2210/pdb9eup/pdb
• Related: 9EUO
• EMDB information: 19978 19979
• Descriptor: Sodium-dependent dopamine transporter, 9D5 ANTIBODY, HEAVY CHAIN, 9D5 ANTIBODY, LIGHT CHAIN, ... (8 entities in total)
• Functional Keywords: slc6a3, dopamine transporter, neurotransmitter sodium symporters, membrane protein
• Biological source: Drosophila melanogaster (fruit fly); More
• Total number of polymer chains: 3
• Total formula weight: 113778.42

Authors

Pedersen, C.N.,Yang, F.,Ita, S.,Xu, Y.,Akunuri, R.,Trampari, S.,Neumann, C.M.T.,Desdorf, L.M.,Schioett, B.,Salvino, J.M.,Mortensen, O.V.,Nissen, P.,Shahsavar, A. (deposition date: 2024-03-27, release date: 2024-07-24, Last modification date: 2024-11-20)

Primary citation

Pedersen, C.N.,Yang, F.,Ita, S.,Xu, Y.,Akunuri, R.,Trampari, S.,Neumann, C.M.T.,Desdorf, L.M.,Schiott, B.,Salvino, J.M.,Mortensen, O.V.,Nissen, P.,Shahsavar, A.
Cryo-EM structure of the dopamine transporter with a novel atypical non-competitive inhibitor bound to the orthosteric site.
J.Neurochem., 168:2043-2055, 2024

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. 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.

PubMed: 39010681
DOI: 10.1111/jnc.16179

Experimental method

ELECTRON MICROSCOPY (3 Å)