{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:18:05Z","timestamp":1785421085525,"version":"3.56.0"},"reference-count":26,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["RS-2024-00440289"],"award-info":[{"award-number":["RS-2024-00440289"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"crossref","award":["RS-2026-25476185"],"award-info":[{"award-number":["RS-2026-25476185"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"crossref"}]},{"award":["RS-2024-00440289"],"award-info":[{"award-number":["RS-2024-00440289"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RS-2026-25476185"],"award-info":[{"award-number":["RS-2026-25476185"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002543","name":"Pusan National University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002543","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/01an57a31","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP24fk0108667"],"award-info":[{"award-number":["JP24fk0108667"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP25fk0108667"],"award-info":[{"award-number":["JP25fk0108667"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP24fk0108669"],"award-info":[{"award-number":["JP24fk0108669"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP25fk0108669"],"award-info":[{"award-number":["JP25fk0108669"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP24ama121005"],"award-info":[{"award-number":["JP24ama121005"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP25ama121005"],"award-info":[{"award-number":["JP25ama121005"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"award":["JP24fk0108667"],"award-info":[{"award-number":["JP24fk0108667"]}],"id":[{"id":"https:\/\/ror.org\/004rtk039","id-type":"ROR","asserted-by":"publisher"}]},{"award":["JP25fk0108667"],"award-info":[{"award-number":["JP25fk0108667"]}],"id":[{"id":"https:\/\/ror.org\/004rtk039","id-type":"ROR","asserted-by":"publisher"}]},{"award":["JP24fk0108669"],"award-info":[{"award-number":["JP24fk0108669"]}],"id":[{"id":"https:\/\/ror.org\/004rtk039","id-type":"ROR","asserted-by":"publisher"}]},{"award":["JP25fk0108669"],"award-info":[{"award-number":["JP25fk0108669"]}],"id":[{"id":"https:\/\/ror.org\/004rtk039","id-type":"ROR","asserted-by":"publisher"}]},{"award":["JP24ama121005"],"award-info":[{"award-number":["JP24ama121005"]}],"id":[{"id":"https:\/\/ror.org\/004rtk039","id-type":"ROR","asserted-by":"publisher"}]},{"award":["JP25ama121005"],"award-info":[{"award-number":["JP25ama121005"]}],"id":[{"id":"https:\/\/ror.org\/004rtk039","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Joint Research Program of the National Institute for Physiological Sciences","award":["25NIPS135"],"award-info":[{"award-number":["25NIPS135"]}]},{"name":"Joint Research Program of the National Institute for Physiological Sciences","award":["24NIPS118"],"award-info":[{"award-number":["24NIPS118"]}]},{"award":["25NIPS135"],"award-info":[{"award-number":["25NIPS135"]}],"id":[{"id":"https:\/\/ror.org\/048v13307","id-type":"ROR","asserted-by":"publisher"}]},{"award":["24NIPS118"],"award-info":[{"award-number":["24NIPS118"]}],"id":[{"id":"https:\/\/ror.org\/048v13307","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Human noroviruses (HuNoVs) are a leading cause of acute gastroenteritis worldwide, yet no effective antiviral therapeutics are currently available. Although environmentally induced capsid conformational changes associated with infectivity have been reported in murine noroviruses (MNVs), comparable conformational switching has not been demonstrated in HuNoVs. In this study, we generated HuNoV GII.3 virus-like particles (VLPs) using a baculovirus expression system and identified two distinct T = 3 particle populations coexisting within VLP preparations derived from a single strain through cryo-electron microscopy single-particle analysis. Comparative structural analysis revealed that these two T = 3 capsid conformations correspond to the resting and rising states of the protruding (P) domain. Rearrangement of the P domain alters intermolecular interactions between adjacent capsid subunits, resulting in distinct capsid surface architectures. In the resting state, intermolecular contacts were mediated predominantly by the P2 subdomain, with limited contribution from the P1 subdomain. In contrast, the rising state exhibited a shift toward an alternative interaction interface primarily involving the P1 subdomain. The alteration of the capsid surface accompanying this conformational switching can influence biologically relevant intermolecular interactions with viral hosts and antibodies as demonstrated in murine norovirus. These findings demonstrate previously unrecognized structural polymorphism in the HuNoV capsid and provide evidence that conformational switching may occur in HuNoVs. Our results offer new insights into norovirus capsid dynamics and may inform future structure-based vaccine and antiviral drug development.<\/jats:p>","DOI":"10.3390\/ijms27156586","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T10:38:41Z","timestamp":1784889521000},"page":"6586","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Conformational Plasticity of the Human Norovirus GII.3 Capsid Reveals Alternative P Domain Interaction Networks"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8628-4267","authenticated-orcid":false,"given":"Chihong","family":"Song","sequence":"first","affiliation":[{"name":"Department of Convergence Medicine, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea"},{"name":"Core Research Facility, Pusan National University, Yangsan 50612, Republic of Korea"},{"name":"Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motohiro","family":"Miki","sequence":"additional","affiliation":[{"name":"Department of Infection Control Science and Immunology, \u014cmura Satoshi Memorial Institute, Kitasato University, Minato-ku, Tokyo 108-0072, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8771-4732","authenticated-orcid":false,"given":"Reiko","family":"Takai-Todaka","sequence":"additional","affiliation":[{"name":"Department of Infection Control Science and Immunology, \u014cmura Satoshi Memorial Institute, Kitasato University, Minato-ku, Tokyo 108-0072, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosuke","family":"Murakami","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Testing and Technology Research, National Institute of Infectious Diseases, Japan Institute of Health Security, Shinjuku-ku, Tokyo 162-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7692-1151","authenticated-orcid":false,"given":"Kazuhiko","family":"Katayama","sequence":"additional","affiliation":[{"name":"Department of Infection Control Science and Immunology, \u014cmura Satoshi Memorial Institute, Kitasato University, Minato-ku, Tokyo 108-0072, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9446-3652","authenticated-orcid":false,"given":"Kazuyoshi","family":"Murata","sequence":"additional","affiliation":[{"name":"Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences, Okazaki 444-8585, Japan"},{"name":"National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki 444-8585, Japan"},{"name":"Department of Physiological Sciences, The Graduate University for Advanced Studies, Okazaki 444-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lopman, B.A. (2016). The vast and varied global burden of norovirus. PLoS Med., 13.","DOI":"10.1371\/journal.pmed.1001999"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1097\/QCO.0000000000000094","article-title":"Norovirus in health-care settings","volume":"27","author":"Lopman","year":"2014","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/s41541-024-00884-2","article-title":"A narrative review of norovirus epidemiology, biology, and challenges to vaccine development","volume":"9","author":"Carlson","year":"2024","journal-title":"npj Vaccines"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1080\/14760584.2018.1510327","article-title":"Progress on norovirus vaccine research: Public health considerations and future directions","volume":"17","author":"Mattison","year":"2018","journal-title":"Expert Rev. Vaccines"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/j.chom.2014.05.015","article-title":"Advances in norovirus biology","volume":"15","author":"Karst","year":"2014","journal-title":"Cell Host Microbe"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1126\/science.286.5438.287","article-title":"X-ray crystallographic structure of the Norwalk virus capsid","volume":"286","author":"Prasad","year":"1999","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Song, C., Takai-Todaka, R., Miki, M., Haga, K., Fujimoto, A., Ishiyama, R., Oikawa, K., Yokoyama, M., Miyazaki, N., and Iwasaki, K. (2020). Dynamic rotation of the protruding domain enhances the infectivity of norovirus. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008619"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e00176-21","DOI":"10.1128\/JVI.00176-21","article-title":"A norovirus uses bile salts to escape antibody recognition while enhancing receptor binding","volume":"95","author":"Williams","year":"2021","journal-title":"J. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e01411-24","DOI":"10.1128\/jvi.01735-23","article-title":"The reversible activation of norovirus by metal ions","volume":"98","author":"Sherman","year":"2024","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1038\/s41467-022-28757-z","article-title":"Atomic structure of the predominant GII.4 human norovirus capsid reveals novel stability and plasticity","volume":"13","author":"Hu","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6516","DOI":"10.1038\/s41467-023-42146-0","article-title":"A single nanobody neutralizes multiple epochally evolving human noroviruses by modulating capsid plasticity","volume":"14","author":"Salmen","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s13099-025-00756-7","article-title":"Increased GII.3 [P12] norovirus outbreaks and viral whole genome analysis in Beijing, China during 2021 and 2023","volume":"17","author":"Fu","year":"2025","journal-title":"Gut Pathog."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e00981-19","DOI":"10.1128\/JVI.00970-19","article-title":"Bile salts alter the mouse norovirus capsid conformation: Implications for cell attachment and immune evasion","volume":"93","author":"Sherman","year":"2019","journal-title":"J. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e00038-25","DOI":"10.1128\/jvi.00219-25","article-title":"Murine norovirus allosteric escape mutants mimic gut activation","volume":"99","author":"Sherman","year":"2025","journal-title":"J. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e2517493122","DOI":"10.1073\/pnas.2517493122","article-title":"Functional diversity in GII.4 norovirus entry: HBGA binding and postattachment infection","volume":"122","author":"Ayyar","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6527","DOI":"10.1128\/jvi.66.11.6527-6532.1992","article-title":"Expression, self-assembly, and antigenicity of the Norwalk virus capsid protein","volume":"66","author":"Jiang","year":"1992","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1111\/1348-0421.12435","article-title":"Effects of disinfectants against norovirus virus-like particles predict norovirus inactivation","volume":"60","author":"Sato","year":"2016","journal-title":"Microbiol. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"E4043","DOI":"10.1073\/pnas.1415096111","article-title":"Plasmid-based human norovirus reverse genetics system produces reporter-tagged progeny virus containing infectious genomic RNA","volume":"111","author":"Katayama","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.jsb.2005.07.007","article-title":"Automated electron microscope tomography using robust prediction of specimen movements","volume":"152","author":"Mastronarde","year":"2005","journal-title":"J. Struct. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4169","DOI":"10.1042\/BCJ20210708","article-title":"New tools for automated cryo-EM single-particle analysis in RELION-4.0","volume":"478","author":"Kimanius","year":"2021","journal-title":"Biochem. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/nmeth.4193","article-title":"MotionCor2: Anisotropic correction of beam-induced motion for improved cryo-electron microscopy","volume":"14","author":"Zheng","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.jsb.2015.08.008","article-title":"CTFFIND4: Fast and accurate defocus estimation from electron micrographs","volume":"192","author":"Rohou","year":"2015","journal-title":"J. Struct. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera-A visualization system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1107\/S0907444910007493","article-title":"Features and development of Coot","volume":"66","author":"Emsley","year":"2010","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1107\/S0907444909052925","article-title":"PHENIX: A comprehensive Python-based system for macromolecular structure solution","volume":"66","author":"Adams","year":"2010","journal-title":"Acta Crystallogr. D Biol. Crystallogr."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6586\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T04:19:32Z","timestamp":1785039572000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6586"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,24]]},"references-count":26,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27156586"],"URL":"https:\/\/doi.org\/10.3390\/ijms27156586","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,24]]}}}