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We present the production in the baculovirus-insect cell system of the VACV DNA polymerase holoenzyme, which consists of the E9 polymerase in combination with its co-factor, the A20-D4 heterodimer. This led to the 3.8 \u00c5 cryo-electron microscopy (cryo-EM) structure of the DNA-free form of the holoenzyme. The model of the holoenzyme was constructed from high-resolution structures of the components of the complex and the A20 structure predicted by AlphaFold 2. The structures do not change in the context of the holoenzyme compared to the previously determined crystal and NMR structures, but the E9 thumb domain became disordered. The E9-A20-D4 structure shows the same compact arrangement with D4 folded back on E9 as observed for the recently solved MPXV holoenzyme structures in the presence and the absence of bound DNA. A conserved interface between E9 and D4 is formed by a cluster of hydrophobic residues. Small-angle X-ray scattering data show that other, more open conformations of E9-A20-D4 without the E9-D4 contact exist in solution using the flexibility of two hinge regions in A20. Biolayer interferometry (BLI) showed that the E9-D4 interaction is indeed weak and transient in the absence of DNA although it is very important, as it has not been possible to obtain viable viruses carrying mutations of key residues within the E9-D4 interface.<\/jats:p>","DOI":"10.1371\/journal.ppat.1011652","type":"journal-article","created":{"date-parts":[[2024,5,20]],"date-time":"2024-05-20T13:47:39Z","timestamp":1716212859000},"page":"e1011652","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Structure and flexibility of the DNA polymerase holoenzyme of vaccinia virus"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0876-6118","authenticated-orcid":true,"given":"Wim P.","family":"Burmeister","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laetitia","family":"Boutin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aurelia C.","family":"Balestra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henri","family":"Gr\u00f6ger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allison","family":"Ballandras-Colas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Hutin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Kraft","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clemens","family":"Grimm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bettina","family":"B\u00f6ttcher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Utz","family":"Fischer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Tarbouriech","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Iseni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,5,20]]},"reference":[{"key":"ppat.1011652.ref001","article-title":"A contemporary review of clade-specific virological differences in monkeypox viruses","author":"T Okwor","year":"2023","journal-title":"Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis"},{"key":"ppat.1011652.ref002","article-title":"APOBEC3F is a mutational driver of the human Monkeypox virus identified in the 2022 outbreak.","author":"R Susp\u00e8ne","year":"2023","journal-title":"J Infect Dis"},{"key":"ppat.1011652.ref003","first-page":"112.e5","article-title":"Transmission characteristics, replication patterns and clinical manifestations of human monkeypox virus-an in-depth analysis of four cases from Germany","volume":"29","author":"D Hornuss","year":"2023","journal-title":"Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis"},{"key":"ppat.1011652.ref004","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1038\/s41564-022-01269-8","article-title":"Tecovirimat is effective against human monkeypox virus in vitro at nanomolar concentrations.","volume":"7","author":"G Frenois-Veyrat","year":"2022","journal-title":"Nat Microbiol."},{"key":"ppat.1011652.ref005","first-page":"1250","article-title":"Monkeypox: A New Challenge for Global Health System?","volume":"13","author":"F Spirito","year":"2023","journal-title":"Life Basel Switz"},{"key":"ppat.1011652.ref006","first-page":"2129","volume-title":"Fields Virology","author":"B. 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