{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T02:45:18Z","timestamp":1772160318986,"version":"3.50.1"},"reference-count":32,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T00:00:00Z","timestamp":1704240000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001868","name":"National Science Council","doi-asserted-by":"publisher","award":["MOST 109\u20102314\u2010B\u2010075\u2010031"],"award-info":[{"award-number":["MOST 109\u20102314\u2010B\u2010075\u2010031"]}],"id":[{"id":"10.13039\/501100001868","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001868","name":"National Science Council","doi-asserted-by":"publisher","award":["MOST\u2010107\u20102314\u2010B\u2010075\u2010049\u2010MY2"],"award-info":[{"award-number":["MOST\u2010107\u20102314\u2010B\u2010075\u2010049\u2010MY2"]}],"id":[{"id":"10.13039\/501100001868","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011912","name":"Taipei Veterans General Hospital","doi-asserted-by":"publisher","award":["V108C\u2010206"],"award-info":[{"award-number":["V108C\u2010206"]}],"id":[{"id":"10.13039\/501100011912","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011912","name":"Taipei Veterans General Hospital","doi-asserted-by":"publisher","award":["V110C\u2010204"],"award-info":[{"award-number":["V110C\u2010204"]}],"id":[{"id":"10.13039\/501100011912","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:p>\n                    HCV NS5A is a dimeric phosphoprotein involved in HCV replication. NS5A inhibitors are among direct\u2010acting antivirals (DAA) for HCV therapy. The Y93H mutant of NS5A is resistant to NS5A inhibitors, but the precise mechanism remains unclear. In this report, we proposed a Ser38\u2010His93\u2010Asn91 triad to dissect the mechanism. Using\n                    <jats:sc>pymol<\/jats:sc>\n                    1.3 software, the homology structure of JFH1 NS5A was determined based on the dimer structure of genotype 1b extracted from the database Protein DataBank (\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.ebi.ac.uk\/pdbsum\">www.ebi.ac.uk\/pdbsum<\/jats:ext-link>\n                    ) with codes\u00a0\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/doi.org\/10.2210\/pdb1ZH1\/pdb\">1ZH1<\/jats:ext-link>\n                    and\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/doi.org\/10.2210\/pdb3FQM\/pdb\">3FQM<\/jats:ext-link>\n                    \/\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/doi.org\/10.2210\/pdb3FQQ\/pdb\">3FQQ<\/jats:ext-link>\n                    . FLAG\u2010NS5A\u2010WT failed to form dimer in the absence of nonstructural proteins from subgenomic replicon (NS3\u20105A); however, FLAG\u2010NS5A\u2010Y93H was able to form dimer without the aid of NS3\u20105A. The Ser38\u2010His93\u2010Asn91 triad in the dimer of the Y93H variant predicts a structural crash of the cleft receiving the NS5A inhibitor daclatasvir. The dimerization assay revealed that the existence of JFH1\u2010NS5A\u2010\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/doi.org\/10.2210\/pdb1ZH1\/pdb\">1ZH1<\/jats:ext-link>\n                    and \u2010\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/doi.org\/10.2210\/pdb3FQM\/pdb\">3FQM<\/jats:ext-link>\n                    homology dimers depended on each other for existence and that both NS5A\u2010WT\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/doi.org\/10.2210\/pdb1ZH1\/pdb\">1ZH1<\/jats:ext-link>\n                    and\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/doi.org\/10.2210\/pdb3FQM\/pdb\">3FQM<\/jats:ext-link>\n                    dimers cooperated to facilitate RNA replication. However, NS5A\u2010Y93H\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/doi.org\/10.2210\/pdb1ZH1\/pdb\">1ZH1<\/jats:ext-link>\n                    alone could form dimer and conduct RNA replication in the absence of the\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/doi.org\/10.2210\/pdb3FQM\/pdb\">3FQM<\/jats:ext-link>\n                    structure. In conclusion, this study provides novel insight into the functional significance of the Ser38\u2010His93\u2010Asn91 triad in resistance of the Y93H variant to NS5A inhibitors.\n                  <\/jats:p>","DOI":"10.1111\/febs.17039","type":"journal-article","created":{"date-parts":[[2023,12,20]],"date-time":"2023-12-20T04:45:44Z","timestamp":1703047544000},"page":"1264-1274","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ser38\u2010His93\u2010Asn91 triad confers resistance of JFH1 HCV NS5A\u2010Y93H variant to NS5A inhibitors"],"prefix":"10.1111","volume":"291","author":[{"given":"Wei\u2010Ping","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Medical Research Taipei Veterans General Hospital  Taiwan"},{"name":"Institute of Biochemistry and Molecular Biology, School of Life Sciences National Yang Ming Chiao Tung University  Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keng\u2010Chang","family":"Tsai","sequence":"additional","affiliation":[{"name":"National Research Institute of Chinese Medicine, Ministry of Health and Welfare  Taipei Taiwan"},{"name":"The Ph.D. Program for Medical Biotechnology, College of Medical Science and Technology Taipei Medical University  Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shi\u2010Xian","family":"Liao","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine Taipei Veterans General Hospital  Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi\u2010Hsiang","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine Taipei Veterans General Hospital  Taiwan"},{"name":"School of Medicine, College of Medicine National Yang Ming Chiao Tung University  Taipei 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