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ZIKV capsid (C) protein, one of three key structural proteins, is essential for viral assembly and encapsidation. In dengue virus, a closely related flavivirus, the homologous C protein interacts with host lipid systems, namely intracellular lipid droplets, for successful viral replication. Here, we investigate ZIKV C interaction with host lipid systems, showing that it binds host lipid droplets but, contrary to expected, in an unspecific manner. Contrasting with other flaviviruses, ZIKV C also does not bind very\u2010low density\u2010lipoproteins. Comparing with other <jats:italic>Flavivirus<\/jats:italic>, capsid proteins show that ZIKV C structure is particularly thermostable and seems to be locked into an auto\u2010inhibitory conformation due to a disordered <jats:italic>N<\/jats:italic>\u2010terminal, hence blocking specific interactions and supporting the experimental differences observed. Such distinct structural features must be considered when targeting capsid proteins in drug development.<\/jats:p>","DOI":"10.1002\/pro.5142","type":"journal-article","created":{"date-parts":[[2024,8,28]],"date-time":"2024-08-28T12:09:10Z","timestamp":1724846950000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Zika virus capsid protein closed structure modulates binding to host lipid systems"],"prefix":"10.1002","volume":"33","author":[{"given":"Ana S.","family":"Martins","sequence":"first","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa  Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filomena A.","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa  Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9 R.","family":"Nascimento","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa  Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelly M.","family":"Silva","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa  Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa V.","family":"Rebelo","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa  Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9 F.","family":"Faustino","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa  Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco J.","family":"Enguita","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa  Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland G.","family":"Huber","sequence":"additional","affiliation":[{"name":"Bioinformatics Institute (BII), Agency for Science Technology and Research (A*STAR)  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuno C.","family":"Santos","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa  Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9284-8599","authenticated-orcid":false,"given":"Ivo C.","family":"Martins","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa  Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,8,28]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000035"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-3697(94)00228-2"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24098158"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(16)00095-5"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.3201\/eid2110.150847"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)00562-6"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.06796-11"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2012.11.007"},{"key":"e_1_2_8_10_1","unstructured":"CDC: Centers for Disease Control and Prevention. 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