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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,5,23]]},"abstract":"<jats:p>Mammalian orthoreoviruses (reoviruses) serve as potential triggers of celiac disease and have oncolytic properties, making these viruses potential cancer therapeutics. Primary attachment of reovirus to host cells is mainly mediated by the trimeric viral protein, \u03c31, which engages cell-surface glycans, followed by high-affinity binding to junctional adhesion molecule-A (JAM-A). This multistep process is thought to be accompanied by major conformational changes in \u03c31, but direct evidence is lacking. By combining biophysical, molecular, and simulation approaches, we define how viral capsid protein mechanics influence virus-binding capacity and infectivity. Single-virus force spectroscopy experiments corroborated by in silico simulations show that GM2 increases the affinity of \u03c31 for JAM-A by providing a more stable contact interface. We demonstrate that conformational changes in \u03c31 that lead to an extended rigid conformation also significantly increase avidity for JAM-A. Although its associated lower flexibility impairs multivalent cell attachment, our findings suggest that diminished \u03c31 flexibility enhances infectivity, indicating that fine-tuning of \u03c31 conformational changes is required to successfully initiate infection. Understanding properties underlying the nanomechanics of viral attachment proteins offers perspectives in the development of antiviral drugs and improved oncolytic vectors.<\/jats:p>","DOI":"10.1073\/pnas.2220741120","type":"journal-article","created":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T15:15:35Z","timestamp":1684163735000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":15,"title":["Deciphering molecular mechanisms stabilizing the reovirus-binding complex"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0123-4760","authenticated-orcid":false,"given":"Rita","family":"dos Santos Natividade","sequence":"first","affiliation":[{"name":"Louvain Institute of Biomolecular Science and Technology, NanoBiophysics lab, Universit\u00e9 catholique de Louvain, 1348 Louvain-la-Neuve, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3042-1749","authenticated-orcid":false,"given":"Melanie","family":"Koehler","sequence":"additional","affiliation":[{"name":"Louvain Institute of Biomolecular Science and Technology, NanoBiophysics lab, Universit\u00e9 catholique de Louvain, 1348 Louvain-la-Neuve, Belgium"},{"name":"Leibniz Institute for Food Systems Biology at the Technical University of Munich, 85354 Freising, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7370-9596","authenticated-orcid":false,"given":"Priscila S. 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