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Here, we present cryo\u2013electron microscopy structures of stabilized HERV-K Env in the prefusion conformation, revealing a distinct fold and architecture compared to HIV and simian immunodeficiency virus. We also generated and characterized a panel of monoclonal antibodies with subunit and conformational specificity, serving as valuable research tools. These antibodies enabled structure determination of the postfusion conformation of HERV-K Env, including its unique \u201ctether\u201d helix, and antibody-bound prefusion Env. Together, these results provide a structural framework that opens the door to mechanistic studies of HERV-K Env and tools for its evaluation as a potential therapeutic target.<\/jats:p>","DOI":"10.1126\/sciadv.ady8168","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T17:59:06Z","timestamp":1756317546000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["Human endogenous retrovirus K (HERV-K) envelope structures in pre- and postfusion by cryo-EM"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5419-060X","authenticated-orcid":true,"given":"Jeremy","family":"Shek","sequence":"first","affiliation":[{"name":"Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA."},{"name":"Dept. of Medicine, University of California, San Diego, La Jolla, CA 92037, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7469-2052","authenticated-orcid":true,"given":"Chen","family":"Sun","sequence":"additional","affiliation":[{"name":"Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0663-906X","authenticated-orcid":true,"given":"Elise M.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA."},{"name":"Dept. of Medicine, University of California, San Diego, La Jolla, CA 92037, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9942-9441","authenticated-orcid":true,"given":"Fatemeh","family":"Moadab","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, University of Washington, Seattle, WA 98109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3406-1210","authenticated-orcid":true,"given":"Kathryn M.","family":"Hastie","sequence":"additional","affiliation":[{"name":"Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roshan R.","family":"Rajamanickam","sequence":"additional","affiliation":[{"name":"Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick J.","family":"Penalosa","sequence":"additional","affiliation":[{"name":"Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA."},{"name":"Dept. of Medicine, University of California, San Diego, La Jolla, CA 92037, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7825-4025","authenticated-orcid":true,"given":"Stephanie S.","family":"Harkins","sequence":"additional","affiliation":[{"name":"Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1972-9462","authenticated-orcid":true,"given":"Diptiben","family":"Parekh","sequence":"additional","affiliation":[{"name":"Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8686-7574","authenticated-orcid":true,"given":"Chitra","family":"Hariharan","sequence":"additional","affiliation":[{"name":"Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8471-469X","authenticated-orcid":true,"given":"Dawid S.","family":"Zyla","sequence":"additional","affiliation":[{"name":"Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassandra","family":"Yu","sequence":"additional","affiliation":[{"name":"Center for Vaccine Innovation, La Jolla Institute for Immunology, La Jolla, CA 92037, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6212-1428","authenticated-orcid":true,"given":"Kelly C. 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