{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:44:22Z","timestamp":1791351862816,"version":"4.3.1"},"reference-count":66,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T00:00:00Z","timestamp":1710806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T00:00:00Z","timestamp":1710806400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100008579","name":"P\u0159\u00edrodov\u011bdeck\u00e1 Fakulta, Univerzita Karlova","doi-asserted-by":"crossref","award":["383821\/2600"],"award-info":[{"award-number":["383821\/2600"]}],"id":[{"id":"10.13039\/100008579","id-type":"DOI","asserted-by":"crossref"}]},{"name":"EC | Horizon 2020 Framework Programme","award":["StG-2017 759661"],"award-info":[{"award-number":["StG-2017 759661"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2024,3,19]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Adenovirus (AdV) infection of the respiratory epithelium is common but poorly understood. Human AdV species C types, such as HAdV-C5, utilize the Coxsackie-adenovirus receptor (CAR) for attachment and subsequently integrins for entry. CAR and integrins are however located deep within the tight junctions in the mucosa where they would not be easily accessible. Recently, a model for CAR-independent AdV entry was proposed. In this model, human lactoferrin (hLF), an innate immune protein, aids the viral uptake into epithelial cells by mediating interactions between the major capsid protein, hexon, and yet unknown host cellular receptor(s). However, a detailed understanding of the molecular interactions driving this mechanism is lacking. Here, we present a new cryo-EM structure of HAdV-5C hexon at high resolution alongside a hybrid structure of HAdV-5C hexon complexed with human lactoferrin (hLF). These structures reveal the molecular determinants of the interaction between hLF and HAdV-C5 hexon. hLF engages hexon primarily\n                      <jats:italic>via<\/jats:italic>\n                      its N-terminal lactoferricin (Lfcin) region, interacting with hexon\u2019s hypervariable region 1 (HVR-1). Mutational analyses pinpoint critical Lfcin contacts and also identify additional regions within hLF that critically contribute to hexon binding. Our study sheds more light on the intricate mechanism by which HAdV-C5 utilizes soluble hLF\/Lfcin for cellular entry. These findings hold promise for advancing gene therapy applications and inform vaccine development.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>Our study delves into the structural aspects of adenovirus (AdV) infections, specifically HAdV-C5 in the respiratory epithelium. It uncovers the molecular details of a novel pathway where human lactoferrin (hLF) interacts with the major capsid protein, hexon, facilitating viral entry, and bypassing traditional receptors such as CAR and integrins. The study\u2019s cryo-EM structures reveal how hLF engages hexon, primarily through its N-terminal lactoferricin (Lfcin) region and hexon\u2019s hypervariable region 1 (HVR-1). Mutational analyses identify critical Lfcin contacts and other regions within hLF vital for hexon binding. This structural insight sheds light on HAdV-C5\u2019s mechanism of utilizing soluble hLF\/Lfcin for cellular entry, holding promise for gene therapy and vaccine development advancements in adenovirus research.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01576-23","type":"journal-article","created":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T09:00:29Z","timestamp":1707296429000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":6,"title":["Structural insights into the interaction between adenovirus C5 hexon and human lactoferrin"],"prefix":"10.1128","volume":"98","author":[{"given":"Arun","family":"Dhillon","sequence":"first","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. David","family":"Persson","sequence":"additional","affiliation":[{"name":"Swedish Veterinary Agency, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander N.","family":"Volkov","sequence":"additional","affiliation":[{"name":"VIB-VUB Center for Structural Biology, Flemish Institute of Biotechnology (VIB), Brussels, Belgium"},{"name":"Jean Jeener NMR Centre, Vrije Universiteit Brussel (VUB), Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hagen","family":"S\u00fclzen","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic"},{"name":"Faculty of Science, Charles University, Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"K\u00e1dek","sequence":"additional","affiliation":[{"name":"Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic"},{"name":"Leibniz Institute of Virology (LIV), Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petr","family":"Pompach","sequence":"additional","affiliation":[{"name":"Biotechnology and Biomedical Center of the Academy of Sciences and Charles University in Vestec, Vestec, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sami","family":"Kere\u00efche","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic"},{"name":"First Faculty of Medicine, Charles University, Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Lep\u0161\u00edk","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarina","family":"Danskog","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology, Ume\u00e5 University, Ume\u00e5, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Uetrecht","sequence":"additional","affiliation":[{"name":"Department of Health Sciences and Biomedicine, Faculty V: School of Life Sciences, CSSB Centre for Structural Systems Biology, Deutsches Elektronen Synchrotron DESY and Leibniz Institute of Virology, Hamburg, University of Siegen, Siegen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"Arnberg","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology, Ume\u00e5 University, Ume\u00e5, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5376-9698","authenticated-orcid":false,"given":"Sebastian","family":"Zoll","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-virology-092818-015550"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1099\/jgv.0.001721"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00052-07"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.25441"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.13576"},{"key":"e_1_3_4_7_2","first-page":"1255","article-title":"[Studies on the rabbit conjunctival cells in vitro (author\u2019s transl)]","volume":"80","author":"Ohnishi Y","year":"1976","unstructured":"Ohnishi Y, Noda S. 1976. 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