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U.S.A."],"published-print":{"date-parts":[[2023,8,8]]},"abstract":"<jats:p>\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    multidrug resistance protein 1 (PfMDR1), an adenosine triphosphate (ATP)-binding cassette (ABC) transporter on the digestive vacuole (DV) membrane of the parasite, is associated with the resistance to antimalarial drugs. To understand the mechanisms of PfMDR1, we determined the cryo-electron microscopy structures of this transporter in different states. The transporter in the apo state shows an inward-facing conformation with a large cavity opening to the cytoplasm. Upon ATP binding and dimerization of the nucleotide-binding domains (NBDs), PfMDR1 displays an outward-facing conformation with a cavity toward the DV lumen. Drug resistance\u2013associated mutations were investigated in both structures for their effects, and Y184F was identified as an allosteric activity-enhancing mutation. The amphiphilic substrate-binding site of PfMDR1 was revealed by the complex structure with the antimalarial drug mefloquine and confirmed by mutagenesis studies. Remarkably, a helical structure was found to hinder NBD dimerization and inhibit PfMDR1 activity. The location of this regulatory domain in the N terminus is different from the well-studied R domain in the internal linker region of other ABC transporter family members. The lack of the phosphorylation site of this domain also suggests a different regulation mechanism.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2219905120","type":"journal-article","created":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T13:48:06Z","timestamp":1690897686000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":22,"title":["The structure of\n                    <i>Plasmodium falciparum<\/i>\n                    multidrug resistance protein 1 reveals an N-terminal regulatory domain"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4463-7882","authenticated-orcid":false,"given":"Kaixue","family":"Si","sequence":"first","affiliation":[{"name":"Harbin Institute of Technology Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1708-3562","authenticated-orcid":false,"given":"Xishuo","family":"He","sequence":"additional","affiliation":[{"name":"Harbin Institute of Technology Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8191-7069","authenticated-orcid":false,"given":"Liping","family":"Chen","sequence":"additional","affiliation":[{"name":"Harbin Institute of Technology Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Harbin Institute of Technology Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changyou","family":"Guo","sequence":"additional","affiliation":[{"name":"Harbin Institute of Technology Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8941-1329","authenticated-orcid":false,"given":"Minghui","family":"Li","sequence":"additional","affiliation":[{"name":"Harbin Institute of Technology Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,8]]},"reference":[{"key":"e_1_3_4_1_2","unstructured":"WHO World malaria report 2021 https:\/\/www.who.int\/teams\/global-malaria-programme\/reports\/world-malaria-report-2021 (World Health Organization Geneva 2021). 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