9euo
From Proteopedia
Outward-open structure of Drosophila dopamine transporter bound to an atypical non-competitive inhibitor
Structural highlights
FunctionDAT_DROME Sodium-dependent dopamine transporter which terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals (PubMed:11125028, PubMed:12606774, PubMed:24037379, PubMed:25970245). Also transports tyramine and norepinephrine, shows less efficient transport of octopamine and does not transport serotonin (PubMed:11125028, PubMed:12606774). Plays a role in the regulation of the rest/activity cycle (PubMed:16093388, PubMed:25232310).[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedThe 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 A 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. Cryo-EM structure of the dopamine transporter with a novel atypical non-competitive inhibitor bound to the orthosteric site.,Pedersen CN, Yang F, Ita S, Xu Y, Akunuri R, Trampari S, Neumann CMT, Desdorf LM, Schiott B, Salvino JM, Mortensen OV, Nissen P, Shahsavar A J Neurochem. 2024 Jul 15. doi: 10.1111/jnc.16179. PMID:39010681[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Drosophila melanogaster | Large Structures | Mus musculus | Akunuri R | Desdorf LM | Ita S | Mortensen OV | Neumann CMT | Nissen P | Pedersen CN | Salvino JM | Schioett B | Shahsavar A | Trampari S | Xu Y | Yang F
