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KRM1 is its only known receptor, but its precise role remains unclear. This study investigates CVA6\u2019s entry mechanism and antibody neutralization. Cryo-EM shows CVA6 clinical strain HeB primarily exists as mature virions. KRM1 binding within the canyon triggers conversion to uncoating intermediate, defining KRM1 as an uncoating receptor for CVA6. However,\n                    <jats:italic>KRM1<\/jats:italic>\n                    knockout reduces CVA6 infectivity without affecting attachment. Conversely, disrupting heparan sulfate proteoglycan (HSPG) impairs both viral attachment and infectivity, and CVA6 virions bind heparin directly. These results support a two-receptor entry model for CVA6: HSPG mediates viral attachment, while KRM1 induces uncoating. Additionally, we develop two CVA6-specific protective antibodies (1F4 and 3H7), targeting a new antigenic site near the three-fold axis of the viral capsid. These antibodies sterically block KRM1 binding and function post-attachment, consistent with KRM1\u2019s role. The findings elucidate CVA6 entry and offer a basis for antibody interventions.\n                  <\/jats:p>","DOI":"10.1038\/s41467-025-67666-9","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T15:05:54Z","timestamp":1766070354000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Molecular mechanisms of receptor recognition and antibody neutralization of coxsackievirus A6"],"prefix":"10.1038","volume":"17","author":[{"given":"Xianliang","family":"Ke","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kexin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weichi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyu","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Shu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8658-9009","authenticated-orcid":false,"given":"Chao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,18]]},"reference":[{"key":"67666_CR1","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s12929-023-00908-4","volume":"30","author":"P Zhu","year":"2023","unstructured":"Zhu, P. et al. 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All other authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"934"}}