{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T19:45:13Z","timestamp":1782848713564,"version":"3.54.5"},"reference-count":59,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the National Key Research and Development Program of China","award":["2024YFC2309200"],"award-info":[{"award-number":["2024YFC2309200"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Norovirus is the leading cause of acute viral gastroenteritis worldwide. While genomic studies have revealed its diversity and evolutionary patterns, the structural mechanisms driving viral adaptation remain poorly understood. Here, we establish a comprehensive structural database of norovirus VP1 P-domains across nine genogroups (GI-GIX) through large-scale AlphaFold2 predictions. By integrating phylogenetic analysis of VP1 sequences and structures, we demonstrate that sequence and structural evolution show overall concordance under purifying selection, yet significant local discrepancies reveal distinct patterns of convergent evolution shaped by structural constraints and functional divergence. Focusing on the predominant GII.4 genotype, we found that compared to near-full-genome and nucleotide trees, only the VP1 amino acid tree reliably clustered GII.4 variants in chronological order as monophyletic groups. We further identify a hierarchical evolutionary strategy: positive selection may drive structural hypervariability in major antigenic epitopes D and C for immune escape, with epitope D exhibiting pronounced structural flexibility that complicates its structural characterization, whereas coevolutionary analysis uncovers a broad network of compensatory interactions spanning multiple epitopes, with striking enrichment in epitope A. These epitopes exhibited a pattern of \u201csequence plasticity with structural conservation\u201d, maintained by coevolutionary constraints that preserve conformational integrity. Together, these findings suggest that norovirus vaccine strategies targeting the structurally conserved conformations of epitopes A and G could overcome the limitations of traditional strain-specific approaches, offering a pathway toward broad protection against evolving viral diversity.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014383","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T18:53:43Z","timestamp":1782845623000},"page":"e1014383","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Balancing under constraint: Structural insights into norovirus evolution and antigenic innovation"],"prefix":"10.1371","volume":"22","author":[{"given":"Yun","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-zi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-yu","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2988-384X","authenticated-orcid":true,"given":"Jie-mei","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"issue":"14","key":"ppat.1014383.ref001","article-title":"Complexities of viral mutation rates","volume":"92","author":"KM Peck","year":"2018","journal-title":"J 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Carugo","year":"2007","journal-title":"Protein Eng Des Sel"},{"issue":"4","key":"ppat.1014383.ref046","doi-asserted-by":"crossref","first-page":"2378","DOI":"10.1128\/JVI.02832-14","article-title":"Structural analysis of a rabbit hemorrhagic disease virus binding to histo-blood group antigens","volume":"89","author":"MM Leuthold","year":"2015","journal-title":"J Virol"},{"issue":"13","key":"ppat.1014383.ref047","doi-asserted-by":"crossref","first-page":"6687","DOI":"10.1128\/JVI.00246-11","article-title":"Crystal structures of GII.10 and GII.12 norovirus protruding domains in complex with histo-blood group antigens reveal details for a potential site of vulnerability","volume":"85","author":"GS Hansman","year":"2011","journal-title":"Journal of Virology"},{"key":"ppat.1014383.ref048","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.vetmic.2015.05.018","article-title":"Molecular characterization and pathogenicity of a genogroup GVI feline 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