{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T11:07:46Z","timestamp":1785928066841,"version":"3.56.0"},"reference-count":68,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T00:00:00Z","timestamp":1721001600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["MH106912"],"award-info":[{"award-number":["MH106912"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["MH121453"],"award-info":[{"award-number":["MH121453"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30\u00a0CA010815\u201053"],"award-info":[{"award-number":["P30\u00a0CA010815\u201053"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 DA051205\u201003"],"award-info":[{"award-number":["R01 DA051205\u201003"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["S10OD030245\u201001"],"award-info":[{"award-number":["S10OD030245\u201001"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002739","name":"Aarhus Universitets Forskningsfond","doi-asserted-by":"publisher","award":["AUFF\u2010E\u20102022\u20109\u201024"],"award-info":[{"award-number":["AUFF\u2010E\u20102022\u20109\u201024"]}],"id":[{"id":"10.13039\/501100002739","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF18OC0032608"],"award-info":[{"award-number":["NNF18OC0032608"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF19OC0054875"],"award-info":[{"award-number":["NNF19OC0054875"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003554","name":"Lundbeck Foundation","doi-asserted-by":"publisher","award":["R310\u20102018\u20103713"],"award-info":[{"award-number":["R310\u20102018\u20103713"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003554","name":"Lundbeck Foundation","doi-asserted-by":"publisher","award":["R368\u20102021\u2010522"],"award-info":[{"award-number":["R368\u20102021\u2010522"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The regulation of dopamine (DA) removal from the synaptic cleft is a crucial process in neurotransmission and is facilitated by the sodium\u2010 and chloride\u2010coupled 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\u2010like rewarding effects and offer a promising strategy for the treatment of drug use disorders. Here, we present the 3.2\u2009\u00c5 resolution cryo\u2010electron microscopy structure of the\n                    <jats:italic>Drosophila melanogaster<\/jats:italic>\n                    dopamine transporter (dDAT) in complex with the atypical non\u2010competitive inhibitor AC\u20104\u2010248. 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\u2010competitive inhibition of DAT and attenuation of cocaine potency by AC\u20104\u2010248 and provide a basis for the rational design of more efficacious atypical inhibitors.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16179-fig-0004-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.16179","type":"journal-article","created":{"date-parts":[[2024,7,16]],"date-time":"2024-07-16T01:45:18Z","timestamp":1721094318000},"page":"2043-2055","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Cryo\u2010\n                    <scp>EM<\/scp>\n                    structure of the dopamine transporter with a novel atypical non\u2010competitive inhibitor bound to the orthosteric site"],"prefix":"10.1111","volume":"168","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9294-7718","authenticated-orcid":false,"given":"Clara Nautrup","family":"Pedersen","sequence":"first","affiliation":[{"name":"DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics Aarhus University  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuyu","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Ita","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibin","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravikumar","family":"Akunuri","sequence":"additional","affiliation":[{"name":"The Wistar Institute  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Trampari","sequence":"additional","affiliation":[{"name":"DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics Aarhus University  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline Marie Teresa","family":"Neumann","sequence":"additional","affiliation":[{"name":"DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics Aarhus University  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3290-3869","authenticated-orcid":false,"given":"Lasse Messell","family":"Desdorf","sequence":"additional","affiliation":[{"name":"Department of Chemistry Aarhus University  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Schi\u00f8tt","sequence":"additional","affiliation":[{"name":"Department of Chemistry Aarhus University  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph M.","family":"Salvino","sequence":"additional","affiliation":[{"name":"The Wistar Institute  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3487-8239","authenticated-orcid":false,"given":"Ole Valente","family":"Mortensen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0948-6628","authenticated-orcid":false,"given":"Poul","family":"Nissen","sequence":"additional","affiliation":[{"name":"DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics Aarhus University  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5405-597X","authenticated-orcid":false,"given":"Azadeh","family":"Shahsavar","sequence":"additional","affiliation":[{"name":"DANDRITE, Nordic EMBL Partnership for Molecular Medicine, Department of Molecular Biology and Genetics Aarhus University  Aarhus Denmark"},{"name":"Department of Drug Design and Pharmacology University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,7,15]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1107\/S2059798318006551"},{"issue":"6","key":"e_1_2_10_3_1","first-page":"634","article-title":"Functional characterization of the dopaminergic psychostimulant Sydnocarb as an allosteric modulator of the human dopamine transporter","volume":"9","author":"Aggarwal S.","year":"2021","journal-title":"Biomedicine"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.9b00262"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpph.32"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.6b00164"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.ADM.0000435321.39251.d7"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.2000.00155.x"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0152-y"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3493"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2004.02386.x"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0600905103"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature17629"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1107\/S2059798318002425"},{"issue":"2","key":"e_1_2_10_15_1","first-page":"52","article-title":"Developing treatments for stimulant abuse: A brief overview","volume":"26","author":"Davidson C.","year":"2016","journal-title":"East Asian Archives of Psychiatry"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444910007493"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2020105164"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm051256o"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-0173(97)00063-5"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3235"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.173"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2007.08.003"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(02)00470-9"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.10613"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.3c00044"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2022110735"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2016.12.004"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407737102"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2003.08.065"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.2174\/092986712803988839"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1107\/S2052252519007619"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M800475200"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.110.171629"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3986"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.108.000869"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1080\/19371918.2013.759005"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0026-895X(24)12754-X"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.1c00302"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2894"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(92)90178-L"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2013.00260"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.04060.x"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04814-x"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct100578z"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12533"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15292-y"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25363-3"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.59.1.83"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4169"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-020-00990-8"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1124\/molpharm.121.000400"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10822-013-9644-8"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0025790"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.4.10.2197154"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03274-z"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2009.08.011"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature06038"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct200133y"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.342212"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1061"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1086\/302132"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12648"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14431"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03978"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abl3857"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9CP05764A"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1602"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.2174\/187152708786927877"}],"container-title":["Journal of Neurochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.16179","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T09:31:51Z","timestamp":1737451911000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jnc.16179"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,15]]},"references-count":68,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2024,9]]}},"alternative-id":["10.1111\/jnc.16179"],"URL":"https:\/\/doi.org\/10.1111\/jnc.16179","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1111\/JNC.16179\/v3\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.16179\/v3\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.16179\/v2\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.16179\/v2\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.16179\/v3\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.16179\/v3\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.16179\/v2\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.16179\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.16179\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.16179\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNC.16179\/v1\/review2","asserted-by":"object"}]},"ISSN":["0022-3042","1471-4159"],"issn-type":[{"value":"0022-3042","type":"print"},{"value":"1471-4159","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,15]]},"assertion":[{"value":"2024-03-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}