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Among them, monkeypox virus (MPXV) has been responsible for two recent public health emergencies as declared by the World Health Organization\n                    <jats:sup>1<\/jats:sup>\n                    . The MPXV polymerase comprises three subunits\u2014a catalytic subunit (F8) and a heterodimeric processivity factor (A22 and E4). The viral polymerase must coordinate activities with the hexameric helicase\u2013primase (E5) to initiate replication of the viral genome\n                    <jats:sup>2<\/jats:sup>\n                    . Although structures of MPXV E5\u00a0(refs.\u00a0\n                    <jats:sup>3,4<\/jats:sup>\n                    ) and the polymerase\n                    <jats:sup>5\u20137<\/jats:sup>\n                    in isolation are available, how they assemble into a functional replisome remains unclear. In isolation, E5 is in an autoinhibited conformation and has very weak helicase activity\n                    <jats:sup>3,4<\/jats:sup>\n                    , and the mechanism for helicase activation is unclear. Here we used cryo-electron microscopy to determine the structures of DNA-bound MPXV replisomes comprising the polymerase holoenzyme (F8, A22 and E4) and the E5 helicase hexamer. We show that, during replisome assembly, E5 undergoes large-scale conformational changes that allow two of its primase domains to interact with the polymerase F8 thumb and A22 subunit. Biochemical assays and single-molecule experiments reveal that this E5 conformational change is coupled to helicase activation and enhances primase activity. Taken together, these findings identify fundamental mechanisms governing coordinated helicase and polymerase activities during DNA replication for an important class of viral pathogens.\n                  <\/jats:p>","DOI":"10.1038\/s41586-026-10937-2","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T15:03:51Z","timestamp":1788361431000},"page":"547-555","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structure and operating principles of a monkeypox virus replisome"],"prefix":"10.1038","volume":"658","author":[{"given":"Zishuo","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pradeep","family":"Sathyanarayana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6051-3786","authenticated-orcid":false,"given":"Joel M. 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