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Structure paper

TitleStructural basis of DNA replication fidelity of the Mpox virus.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 122, Issue 10, Page e2411686122, Year 2025
Publish dateMar 11, 2025
AuthorsYufeng Xie / Lu Kuai / Qi Peng / Qian Wang / Han Wang / Xiaomei Li / Jianxun Qi / Qiang Ding / Yi Shi / George F Gao /
PubMed AbstractThe Mpox virus (MPXV) is an orthopoxvirus that caused a global outbreak in 2022. The poxvirus DNA polymerase complex is responsible for the replication and integrity of the viral genome; however, the ...The Mpox virus (MPXV) is an orthopoxvirus that caused a global outbreak in 2022. The poxvirus DNA polymerase complex is responsible for the replication and integrity of the viral genome; however, the molecular mechanisms underlying DNA replication fidelity are still unclear. In this study, we determined the cryoelectron microscopy (cryo-EM) structures of the MPXV F8-A22-E4 polymerase holoenzyme in its editing state, in complex with mismatched primer-template DNA and DNA containing uracil deoxynucleotide. We showed that the MPXV polymerase has a similar replication-to-edit transition mechanism to proofread the mismatched nucleotides like the B-family DNA polymerases of other species. The unique processivity cofactor A22-E4 undergoes conformational changes in different working states and might affect the proofreading process. Moreover, we elucidated the base excision repair (BER) function of E4 as a uracil-DNA glycosylase and the coupling mechanism of genome replication and BER, characteristic of poxviruses. Our findings greatly enhance our molecular understanding of DNA replication fidelity of orthopoxviruses and will stimulate the development of broad-spectrum antiviral drugs.
External linksProc Natl Acad Sci U S A / PubMed:40035768 / PubMed Central
MethodsEM (single particle)
Resolution2.39 - 3.08 Å
Structure data

62196

9k9r

EMDB-62196, PDB-9k9r:
MPXV DNA polymerase in complex with primer/5U template DNA
Method: EM (single particle) / Resolution: 2.61 Å

62197

9k9s

EMDB-62197, PDB-9k9s:
MPXV DNA polymerase in complex with primer/4U template DNA
Method: EM (single particle) / Resolution: 2.39 Å

62198

9k9t

EMDB-62198, PDB-9k9t:
MPXV DNA polymerase in complex with CDV
Method: EM (single particle) / Resolution: 2.96 Å

62199

9k9u

EMDB-62199, PDB-9k9u:
MPXV DNA polymerase complex in editing state 1
Method: EM (single particle) / Resolution: 3.08 Å

62200

9k9v

EMDB-62200, PDB-9k9v:
MPXV DNA polymerase complex in editing state 2
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-TTP:
THYMIDINE-5'-TRIPHOSPHATE

Source
  • monkeypox virus
KeywordsREPLICATION/DNA / complex / replicate / DNA / mpox / polymerase / REPLICATION-DNA complex

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