{"doi":"10.1111/jnc.16179","title":"Cryo‐ <scp>EM</scp> structure of the dopamine transporter with a novel atypical non‐competitive inhibitor bound to the orthosteric site","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.","journal":"Journal of Neurochemistry","year":2024,"id":432371,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9655,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1237395,"name":"Fuyu Yang","orcid":null,"position":1,"is_corresponding":false},{"id":1237396,"name":"Samantha Ita","orcid":null,"position":2,"is_corresponding":false},{"id":253496,"name":"Yibin Xu","orcid":"0000-0002-8261-3286","position":3,"is_corresponding":false},{"id":1236947,"name":"Ravikumar Akunuri","orcid":"0000-0003-4898-5753","position":4,"is_corresponding":false},{"id":1236948,"name":"Sofia Trampari","orcid":"0000-0002-1291-8092","position":5,"is_corresponding":false},{"id":479343,"name":"Caroline Neumann","orcid":"0000-0003-1574-1760","position":6,"is_corresponding":false},{"id":1236949,"name":"Lasse Messell Desdorf","orcid":"0009-0004-3290-3869","position":7,"is_corresponding":false},{"id":308952,"name":"Birgit Schiøtt","orcid":"0000-0001-9937-1562","position":8,"is_corresponding":false},{"id":348575,"name":"Joseph M. Salvino","orcid":"0000-0002-2184-5980","position":9,"is_corresponding":false},{"id":738289,"name":"Ole V. Mortensen","orcid":"0000-0002-3487-8239","position":10,"is_corresponding":false},{"id":345804,"name":"Poul Nissen","orcid":"0000-0003-0948-6628","position":11,"is_corresponding":false},{"id":1236950,"name":"Azadeh Shahsavar","orcid":"0000-0001-5405-597X","position":12,"is_corresponding":false},{"id":1236946,"name":"Clara Nautrup Pedersen","orcid":"0009-0007-9294-7718","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T01:59:35.267142Z","pmid":"39010681","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}