{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T02:47:04Z","timestamp":1791600424581,"version":"4.3.4"},"reference-count":60,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"16","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2023,4,21]]},"abstract":"<jats:p>The ongoing global pandemic caused by a variant of the monkeypox (or mpox) virus (MPXV) has prompted widespread concern. The MPXV DNA polymerase holoenzyme, consisting of F8, A22, and E4, is vital for replicating the viral genome and represents a crucial target for the development of antiviral drugs. However, the assembly and working mechanism for the DNA polymerase holoenzyme of MPXV remains elusive. Here, we present the cryo\u2013electron microscopy (cryo-EM) structure of the DNA polymerase holoenzyme at an overall resolution of 3.5 \u00c5. Unexpectedly, the holoenzyme is assembled as a dimer of heterotrimers, of which the extra interface between the thumb domain of F8 and A22 shows a clash between A22 and substrate DNA, suggesting an autoinhibition state. Addition of exogenous double-stranded DNA shifts the hexamer into trimer exposing DNA binding sites, potentially representing a more active state. Our findings provide crucial steps toward developing targeted antiviral therapies for MPXV and related viruses.<\/jats:p>","DOI":"10.1126\/sciadv.adg2331","type":"journal-article","created":{"date-parts":[[2023,4,19]],"date-time":"2023-04-19T13:58:40Z","timestamp":1681912720000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":23,"title":["Structural basis for the assembly of the DNA polymerase holoenzyme from a monkeypox virus variant"],"prefix":"10.1126","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3245-3023","authenticated-orcid":true,"given":"Yaning","family":"Li","sequence":"first","affiliation":[{"name":"Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province 310024, China."},{"name":"Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1833-5880","authenticated-orcid":true,"given":"Yaping","family":"Shen","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province 310024, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5651-8317","authenticated-orcid":true,"given":"Ziwei","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Key University Laboratory of Metabolism and Health of Guangdong, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong Province 518055, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7122-6547","authenticated-orcid":true,"given":"Renhong","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Key University Laboratory of Metabolism and Health of Guangdong, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong Province 518055, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00775-4"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bsheal.2022.11.001"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1099"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/br.37.1.1-18.1973"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.281.22.2127"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.81215-0"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.3390\/v12111257"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0007791"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01907-y"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2022.10802"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/17.3.643"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens11080924"},{"key":"e_1_3_3_14_2","first-page":"93","article-title":"The enzymology of poxvirus DNA replication","volume":"163","author":"Traktman P.","year":"1990","unstructured":"P.\u00a0Traktman, The enzymology of poxvirus DNA replication. 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