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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,10,27]]},"abstract":"<jats:p>Bovine viral diarrhea virus (BVDV) is a major contagious pathogen of ruminants and imposes substantial economic burdens on the global livestock industry. The viral envelope glycoprotein E2 mediates host cell attachment by recognizing the CD46 receptor; however, the molecular basis of this interaction remains unclear. Here, we report the crystal structure of BVDV-1 E2 in complex with bovine CD46 at 3.1-\u00c5 resolution. The structure reveals that the SCR1-2 domains of CD46 engage the DII-DIV domains of E2 in a roughly antiparallel orientation. Atomic interactions at the E2\/CD46 interface are dominated by van der Waals contacts, accompanied by only a limited number of hydrogen bonds, which explains the observed low-affinity binding between the two molecules. Structural analysis and mutagenesis studies identify key receptor features that govern host susceptibility to the virus and propose an interesting bipartite model: The D\u2032\/D interloop within SCR1 of CD46 likely serves as the \u201cmolecular determinant,\u201d and key interface residues within SCR2 function as the \u201caffinity regulator.\u201d We further engineered CD46 decoy proteins exhibiting over 1,800-fold higher apparent binding to E2 than the wild-type receptor and demonstrated their potent virus-neutralizing activity. Collectively, these findings elucidate the molecular basis of CD46 recognition by BVDV, provide a structural framework for understanding the viral host range, and establish a receptor-based strategy for potential antiviral intervention.<\/jats:p>","DOI":"10.1073\/pnas.2620643123","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:01:52Z","timestamp":1792519312000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Structure of bovine viral diarrhea virus E2 glycoprotein in complex with CD46 reveals the molecular basis of virus\u2013receptor recognition"],"prefix":"10.1073","volume":"123","author":[{"given":"Yanping","family":"Duan","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/011ashp19","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Emergency Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan 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