{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T21:15:06Z","timestamp":1791321306030,"version":"4.3.1"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,8,18]],"date-time":"2017-08-18T00:00:00Z","timestamp":1503014400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,8,18]],"date-time":"2017-08-18T00:00:00Z","timestamp":1503014400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The human cytomegalovirus (HCMV) terminase complex consists of several components acting together to cleave viral DNA into unit length genomes and translocate them into capsids, a critical process in the production of infectious virions subsequent to DNA replication. Previous studies suggest that the carboxyl-terminal portion of the pUL56 subunit interacts with the pUL89 subunit. However, the specific interacting residues of pUL56 remain unknown. We identified a conserved sequence in the C-terminal moiety of pUL56 (<jats:sub>671<\/jats:sub>WMVVKYMGFF<jats:sub>680<\/jats:sub>). Overrepresentation of conserved aromatic amino acids through 20 herpesviruses homologues of pUL56 suggests an involvement of this short peptide into the interaction between the larger pUL56 terminase subunit and the smaller pUL89 subunit. Use of Alpha technology highlighted an interaction between pUL56 and pUL89 driven through the peptide <jats:sub>671<\/jats:sub>WMVVKYMGFF<jats:sub>680<\/jats:sub>. A deletion of these residues blocks viral replication. We hypothesize that it is the consequence of the disruption of the pUL56-pUL89 interaction. These results show that this motif is essential for HCMV replication and could be a target for development of new small antiviral drugs or peptidomimetics.<\/jats:p>","DOI":"10.1038\/s41598-017-09469-7","type":"journal-article","created":{"date-parts":[[2017,8,14]],"date-time":"2017-08-14T14:05:39Z","timestamp":1502719539000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Identification of a short sequence in the HCMV terminase pUL56 essential for interaction with pUL89 subunit"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1237-1936","authenticated-orcid":false,"given":"G.","family":"Ligat","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Jacquet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Chou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Couvreux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Alain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Hantz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,8,18]]},"reference":[{"key":"9469_CR1","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1002\/jmv.20127","volume":"73","author":"S Alain","year":"2004","unstructured":"Alain, S. et al. Detection of ganciclovir resistance after valacyclovir-prophylaxis in renal transplant recipients with active cytomegalovirus infection. J. Med. Virol. \n                           73, 566\u2013573 (2004).","journal-title":"J. Med. Virol."},{"key":"9469_CR2","doi-asserted-by":"publisher","first-page":"2628","DOI":"10.1093\/jac\/dkq368","volume":"65","author":"S Hantz","year":"2010","unstructured":"Hantz, S. et al. Drug-resistant cytomegalovirus in transplant recipients: a French cohort study. J. Antimicrob. Chemother. \n                           65, 2628\u20132640 (2010).","journal-title":"J. Antimicrob. Chemother."},{"key":"9469_CR3","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1128\/AAC.01596-09","volume":"54","author":"P Lischka","year":"2010","unstructured":"Lischka, P. et al. In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246. Antimicrob. Agents Chemother. \n                           54, 1290\u20131297 (2010).","journal-title":"Antimicrob. Agents Chemother."},{"key":"9469_CR4","first-page":"269","volume":"8","author":"DP Melendez","year":"2015","unstructured":"Melendez, D. P. & Razonable, R. R. Letermovir and inhibitors of the terminase complex: a promising new class of investigational antiviral drugs against human cytomegalovirus. Infect. Drug Resist \n                           8, 269\u2013277 (2015).","journal-title":"Infect. Drug Resist"},{"key":"9469_CR5","doi-asserted-by":"publisher","first-page":"2065","DOI":"10.1128\/JVI.01967-07","volume":"82","author":"EM Borst","year":"2008","unstructured":"Borst, E. M., Wagner, K., Binz, A., Sodeik, B. & Messerle, M. The essential human cytomegalovirus gene UL52 is required for cleavage-packaging of the viral genome. J. Virol. \n                           82, 2065\u20132078 (2008).","journal-title":"J. Virol."},{"key":"9469_CR6","doi-asserted-by":"publisher","first-page":"1720","DOI":"10.1128\/JVI.01955-12","volume":"87","author":"EM Borst","year":"2013","unstructured":"Borst, E. M. et al. The human cytomegalovirus UL51 protein is essential for viral genome cleavage-packaging and interacts with the terminase subunits pUL56 and pUL89. J. Virol. \n                           87, 1720\u20131732 (2013).","journal-title":"J. Virol."},{"key":"9469_CR7","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00384-16","author":"EM Borst","year":"2016","unstructured":"Borst, E. M. et al. The Essential Human Cytomegalovirus Proteins pUL77 and pUL93 are Structural Components Necessary for Viral Genome Encapsidation. J. Virol, doi:10.1128\/JVI.00384-16 (2016).","journal-title":"J. Virol"},{"key":"9469_CR8","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00351-16","author":"P K\u00f6ppen-Rung","year":"2016","unstructured":"K\u00f6ppen-Rung, P., Dittmer, A. & Bogner, E. Intracellular distributions of capsid-associated pUL77 of HCMV and interactions with packaging proteins and pUL93. J. Virol, doi:10.1128\/JVI.00351-16 (2016).","journal-title":"J. Virol"},{"key":"9469_CR9","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02382-15","author":"BM DeRussy","year":"2015","unstructured":"DeRussy, B. M. & Tandon, R. Human cytomegalovirus pUL93 is required for viral genome cleavage and packaging. J. Virol. doi:10.1128\/JVI.02382-15 (2015).","journal-title":"J. Virol"},{"key":"9469_CR10","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00728-16","author":"BM DeRussy","year":"2016","unstructured":"DeRussy, B. M., Boland, M. T. & Tandon, R. Human Cytomegalovirus pUL93 Links Nucleocapsid Maturation and Nuclear Egress. J. Virol, doi:10.1128\/JVI.00728-16 (2016).","journal-title":"J. Virol"},{"key":"9469_CR11","doi-asserted-by":"publisher","first-page":"1426","DOI":"10.1093\/nar\/gkg229","volume":"31","author":"B Scholz","year":"2003","unstructured":"Scholz, B., Rechter, S., Drach, J. C., Townsend, L. B. & Bogner, E. Identification of the ATP-binding site in the terminase subunit pUL56 of human cytomegalovirus. Nucleic Acids Res \n                           31, 1426\u20131433 (2003).","journal-title":"Nucleic Acids Res"},{"key":"9469_CR12","doi-asserted-by":"publisher","first-page":"6943","DOI":"10.1074\/jbc.M108984200","volume":"277","author":"J-S Hwang","year":"2002","unstructured":"Hwang, J.-S. & Bogner, E. ATPase activity of the terminase subunit pUL56 of human cytomegalovirus. J. Biol. Chem. \n                           277, 6943\u20136948 (2002).","journal-title":"J. Biol. Chem."},{"key":"9469_CR13","doi-asserted-by":"publisher","first-page":"8855","DOI":"10.1021\/bi0600796","volume":"45","author":"C Thoma","year":"2006","unstructured":"Thoma, C. et al. Identification of the interaction domain of the small terminase subunit pUL89 with the large subunit pUL56 of human cytomegalovirus. Biochemistry (Mosc.) \n                           45, 8855\u20138863 (2006).","journal-title":"Biochemistry (Mosc.)"},{"key":"9469_CR14","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1002\/prot.22669","volume":"78","author":"A Couvreux","year":"2010","unstructured":"Couvreux, A. et al. Insight into the structure of the pUL89 C-terminal domain of the human cytomegalovirus terminase complex. Proteins \n                           78, 1520\u20131530 (2010).","journal-title":"Proteins"},{"key":"9469_CR15","doi-asserted-by":"publisher","first-page":"16078","DOI":"10.1073\/pnas.1007144107","volume":"107","author":"M Nadal","year":"2010","unstructured":"Nadal, M. et al. Structure and inhibition of herpesvirus DNA packaging terminase nuclease domain. Proc. Natl. Acad. Sci. USA \n                           107, 16078\u201316083 (2010).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"9469_CR16","doi-asserted-by":"publisher","first-page":"2720","DOI":"10.1016\/S0006-3495(02)75613-0","volume":"82","author":"M Eilers","year":"2002","unstructured":"Eilers, M., Patel, A. B., Liu, W. & Smith, S. O. Comparison of helix interactions in membrane and soluble alpha-bundle proteins. Biophys. J. \n                           82, 2720\u20132736 (2002).","journal-title":"Biophys. J."},{"key":"9469_CR17","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1002\/prot.20593","volume":"61","author":"S Ansari","year":"2005","unstructured":"Ansari, S. & Helms, V. Statistical analysis of predominantly transient protein-protein interfaces. Proteins \n                           61, 344\u2013355 (2005).","journal-title":"Proteins"},{"key":"9469_CR18","doi-asserted-by":"publisher","first-page":"1695","DOI":"10.1093\/nar\/30.7.1695","volume":"30","author":"H Scheffczik","year":"2002","unstructured":"Scheffczik, H., Savva, C. G. W., Holzenburg, A., Kolesnikova, L. & Bogner, E. The terminase subunits pUL56 and pUL89 of human cytomegalovirus are DNA-metabolizing proteins with toroidal structure. Nucleic Acids Res \n                           30, 1695\u20131703 (2002).","journal-title":"Nucleic Acids Res"},{"key":"9469_CR19","doi-asserted-by":"publisher","first-page":"2375","DOI":"10.1099\/vir.0.013250-0","volume":"90","author":"AJ Bradley","year":"2009","unstructured":"Bradley, A. J. et al. High-throughput sequence analysis of variants of human cytomegalovirus strains Towne and AD169. J. Gen. Virol. \n                           90, 2375\u20132380 (2009).","journal-title":"J. Gen. Virol."},{"key":"9469_CR20","doi-asserted-by":"publisher","first-page":"5426","DOI":"10.1073\/pnas.91.12.5426","volume":"91","author":"EF Ullman","year":"1994","unstructured":"Ullman, E. F. et al. Luminescent oxygen channeling immunoassay: measurement of particle binding kinetics by chemiluminescence. Proc. Natl. Acad. Sci. USA \n                           91, 5426\u20135430 (1994).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"9469_CR21","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/j.jviromet.2010.01.020","volume":"165","author":"H Waller","year":"2010","unstructured":"Waller, H., Chatterji, U., Gallay, P., Parkinson, T. & Targett-Adams, P. The use of AlphaLISA technology to detect interaction between hepatitis C virus-encoded NS5A and cyclophilin A. J. Virol. Methods \n                           165, 202\u2013210 (2010).","journal-title":"J. Virol. Methods"},{"key":"9469_CR22","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1177\/135965350801300504","volume":"13","author":"G Champier","year":"2008","unstructured":"Champier, G. et al. Putative functional domains of human cytomegalovirus pUL56 involved in dimerization and benzimidazole D-ribonucleoside activity. Antivir. Ther. \n                           13, 643\u2013654 (2008).","journal-title":"Antivir. Ther."},{"key":"9469_CR23","doi-asserted-by":"publisher","first-page":"2231","DOI":"10.1099\/0022-1317-81-9-2231","volume":"81","author":"K Giesen","year":"2000","unstructured":"Giesen, K., Radsak, K. & Bogner, E. The potential terminase subunit of human cytomegalovirus, pUL56, is translocated into the nucleus by its own nuclear localization signal and interacts with importin alpha. J. Gen. Virol \n                           81, 2231\u20132244 (2000).","journal-title":"J. Gen. Virol"},{"key":"9469_CR24","doi-asserted-by":"publisher","first-page":"9077","DOI":"10.1128\/JVI.75.19.9077-9086.2001","volume":"75","author":"I Buerger","year":"2001","unstructured":"Buerger, I. et al. A novel nonnucleoside inhibitor specifically targets cytomegalovirus DNA maturation via the UL89 and UL56 gene products. J. Virol. \n                           75, 9077\u20139086 (2001).","journal-title":"J. Virol."},{"key":"9469_CR25","doi-asserted-by":"publisher","first-page":"10884","DOI":"10.1128\/JVI.05265-11","volume":"85","author":"T Goldner","year":"2011","unstructured":"Goldner, T. et al. The novel anticytomegalovirus compound AIC246 (Letermovir) inhibits human cytomegalovirus replication through a specific antiviral mechanism that involves the viral terminase. J. Virol. \n                           85, 10884\u201310893 (2011).","journal-title":"J. Virol."},{"key":"9469_CR26","doi-asserted-by":"publisher","first-page":"6588","DOI":"10.1128\/AAC.01623-15","volume":"59","author":"S Chou","year":"2015","unstructured":"Chou, S. Rapid In Vitro Evolution of Human Cytomegalovirus UL56 Mutations That Confer Letermovir Resistance. Antimicrob. Agents Chemother. \n                           59, 6588\u20136593 (2015).","journal-title":"Antimicrob. Agents Chemother."},{"key":"9469_CR27","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1517\/13543784.12.8.1269","volume":"12","author":"MP Walker","year":"2003","unstructured":"Walker, M. P., Yao, N. & Hong, Z. Promising candidates for the treatment of chronic hepatitis C. Expert Opin. Investig. Drugs \n                           12, 1269\u20131280 (2003).","journal-title":"Expert Opin. Investig. Drugs"},{"key":"9469_CR28","first-page":"125","volume":"154","author":"MS Chee","year":"1990","unstructured":"Chee, M. S. et al. Analysis of the protein-coding content of the sequence of human cytomegalovirus strain AD169. Curr. Top. Microbiol. Immunol \n                           154, 125\u2013169 (1990).","journal-title":"Curr. Top. Microbiol. Immunol"},{"key":"9469_CR29","doi-asserted-by":"publisher","DOI":"10.1038\/msb.2011.75","volume":"7","author":"F Sievers","year":"2011","unstructured":"Sievers, F. et al. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol. Syst. Biol. \n                           7, 539 (2011).","journal-title":"Mol. Syst. Biol."},{"key":"9469_CR30","doi-asserted-by":"publisher","first-page":"W597","DOI":"10.1093\/nar\/gkt376","volume":"41","author":"H McWilliam","year":"2013","unstructured":"McWilliam, H. et al. Analysis Tool Web Services from the EMBL-EBI. Nucleic Acids Res \n                           41, W597\u2013600 (2013).","journal-title":"Nucleic Acids Res"},{"key":"9469_CR31","doi-asserted-by":"publisher","first-page":"W580","DOI":"10.1093\/nar\/gkv279","volume":"43","author":"W Li","year":"2015","unstructured":"Li, W. et al. The EMBL-EBI bioinformatics web and programmatic tools framework. Nucleic Acids Res \n                           43, W580\u2013584 (2015).","journal-title":"Nucleic Acids Res"},{"key":"9469_CR32","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1038\/nprot.2015.053","volume":"10","author":"LA Kelley","year":"2015","unstructured":"Kelley, L. A., Mezulis, S., Yates, C. M., Wass, M. N. & Sternberg, M. J. E. The Phyre2 web portal for protein modeling, prediction and analysis. Nat. Protoc. \n                           10, 845\u2013858 (2015).","journal-title":"Nat. Protoc."},{"key":"9469_CR33","doi-asserted-by":"crossref","first-page":"8320","DOI":"10.1128\/JVI.73.10.8320-8329.1999","volume":"73","author":"EM Borst","year":"1999","unstructured":"Borst, E. M., Hahn, G., Koszinowski, U. H. & Messerle, M. Cloning of the human cytomegalovirus (HCMV) genome as an infectious bacterial artificial chromosome in Escherichia coli: a new approach for construction of HCMV mutants. J. Virol. \n                           73, 8320\u20138329 (1999).","journal-title":"J. Virol."},{"key":"9469_CR34","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/j.antiviral.2013.02.002","volume":"98","author":"S Hantz","year":"2013","unstructured":"Hantz, S. et al. Novel DNA polymerase mutations conferring cytomegalovirus resistance: input of BAC-recombinant phenotyping and 3D model. Antiviral Res. \n                           98, 130\u2013134 (2013).","journal-title":"Antiviral Res."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-09469-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-09469-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-09469-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T08:55:11Z","timestamp":1671785711000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-09469-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,18]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["9469"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-09469-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8,18]]},"assertion":[{"value":"31 May 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 July 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 August 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"8796"}}