{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T11:07:27Z","timestamp":1776942447007,"version":"3.51.4"},"reference-count":47,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"AMED","doi-asserted-by":"crossref","award":["JP25fk0310525, JP25fk0310533, JP25fk0310547, JP25ak0101271, JP243fa827038"],"award-info":[{"award-number":["JP25fk0310525, JP25fk0310533, JP25fk0310547, JP25ak0101271, JP243fa827038"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"AMED","doi-asserted-by":"crossref","award":["JP25ama121023"],"award-info":[{"award-number":["JP25ama121023"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"name":"JSPS","award":["JP24K02290, JP25K21782, JP23K27415, JP25K21767, JP25K02691"],"award-info":[{"award-number":["JP24K02290, JP25K21782, JP23K27415, JP25K21767, JP25K02691"]}]},{"DOI":"10.13039\/501100020959","name":"JST-Mirai Program","doi-asserted-by":"publisher","award":["JPMJMI22G1"],"award-info":[{"award-number":["JPMJMI22G1"]}],"id":[{"id":"10.13039\/501100020959","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Sodium taurocholate cotransporting polypeptide (NTCP) is a hepatic transmembrane (TM) protein that functions both as a bile acid transporter and as a host receptor for hepatitis B and D viruses via the viral preS1 binding. The structural and mechanistical determinants for NTCP\u2019s dual functions remain largely undefined. In this study, using comprehensive structure-guided alanine-scanning mutagenesis based on the cryo-electron microscopy structure of the preS1\/NTCP complex, we identified 13, 8 and 9 NTCP amino acid residues critical for viral infection, preS1 binding, and bile acid transport, respectively. Key residues overlappingly regulating viral receptor and transporter functions were located primarily at TM1 and TM8, whereas TM5 and outer-surface NTCP loops mediated viral receptor-specific activity. In addition to 8 amino acids key to preS1 binding, 5 residues likely acted at a post-preS1 binding step of infection. We further found naturally-occurring single nucleotide polymorphism-associated F274C\/S NTCP variants abolished viral receptor function, via the potential conformational changes in bile acid tunnel and outer-surface hollow, as analyzed by molecular dynamics simulations. Our domain-specific structural-functional map of NTCP defines the mechanism how NTCP\u2019s dual functionality is separately regulated, and provides a framework for designing selective antiviral agents that preserve bile acid transport.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013824","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T18:49:20Z","timestamp":1768589360000},"page":"e1013824","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Structural mapping of NTCP distinguishes its dual functionality as a hepatitis B virus receptor and bile acid transporter"],"prefix":"10.1371","volume":"22","author":[{"given":"Kayo","family":"Matsuzawa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toru","family":"Ekimoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chisa","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaho","family":"Shionoya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junki","family":"Mifune","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Morita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junko 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(Baltimore)"},{"issue":"31","key":"ppat.1013824.ref008","doi-asserted-by":"crossref","first-page":"11853","DOI":"10.1074\/jbc.RA118.007179","article-title":"Increased sulfation of bile acids in mice and human subjects with sodium taurocholate cotransporting polypeptide deficiency","volume":"294","author":"F Mao","year":"2019","journal-title":"J Biol Chem"},{"issue":"4","key":"ppat.1013824.ref009","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1002\/hep.27608","article-title":"The p.Ser267Phe variant in SLC10A1 is associated with resistance to chronic hepatitis B","volume":"61","author":"L Peng","year":"2015","journal-title":"Hepatology"},{"issue":"9","key":"ppat.1013824.ref010","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1136\/gutjnl-2015-310686","article-title":"The rs2296651 (S267F) variant on NTCP (SLC10A1) is inversely associated with chronic hepatitis B and progression to cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis 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