9EUP

Inhibitor-free outward-open structure of Drosophila dopamine transporter

9EUP の概要

• エントリーDOI: 10.2210/pdb9eup/pdb
• 関連するPDBエントリー: 9EUO
• EMDBエントリー: 19978 19979
• 分子名称: Sodium-dependent dopamine transporter, 9D5 ANTIBODY, HEAVY CHAIN, 9D5 ANTIBODY, LIGHT CHAIN, ... (8 entities in total)
• 機能のキーワード: slc6a3, dopamine transporter, neurotransmitter sodium symporters, membrane protein
• 由来する生物種: Drosophila melanogaster (fruit fly); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 113778.42

構造登録者

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. (登録日: 2024-03-27, 公開日: 2024-07-24, 最終更新日: 2024-11-20)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (3 Å)