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TitleStructural basis of human mpox viral DNA replication inhibition by brincidofovir and cidofovir.
Journal, issue, pagesInt J Biol Macromol, Vol. 270, Issue Pt 2, Page 132231, Year 2024
Publish dateMay 10, 2024
AuthorsYunxia Xu / Yaqi Wu / Xiaoying Wu / Yuanyuan Zhang / Yaxue Yang / Danyang Li / Biao Yang / Kaiting Gao / Zhengyu Zhang / Changjiang Dong /
PubMed AbstractMpox virus has wildly spread over 108 non-endemic regions in the world since May 2022. DNA replication of mpox is performed by DNA polymerase machinery F8-A22-E4, which is known as a great drug ...Mpox virus has wildly spread over 108 non-endemic regions in the world since May 2022. DNA replication of mpox is performed by DNA polymerase machinery F8-A22-E4, which is known as a great drug target. Brincidofovir and cidofovir are reported to have broad-spectrum antiviral activity against poxviruses, including mpox virus in animal models. However, the molecular mechanism is not understood. Here we report cryogenic electron microscopy structures of mpox viral F8-A22-E4 in complex with a DNA duplex, or dCTP and the DNA duplex, or cidofovir diphosphate and the DNA duplex at resolution of 3.22, 2.98 and 2.79 Å, respectively. Our structural work and DNA replication inhibition assays reveal that cidofovir diphosphate is located at the dCTP binding position with a different conformation to compete with dCTP to incorporate into the DNA and inhibit DNA synthesis. Conformation of both F8-A22-E4 and DNA is changed from the pre-dNTP binding state to DNA synthesizing state after dCTP or cidofovir diphosphate is bound, suggesting a coupling mechanism. This work provides the structural basis of DNA synthesis inhibition by brincidofovir and cidofovir, providing a rational strategy for new therapeutical development for mpox virus and other pox viruses.
External linksInt J Biol Macromol / PubMed:38735603
MethodsEM (single particle)
Resolution2.79 - 3.22 Å
Structure data

36061

8j86

EMDB-36061, PDB-8j86:
Monkeypox virus DNA replication holoenzyme F8, A22 and E4 complex in a DNA binding form
Method: EM (single particle) / Resolution: 3.22 Å

36068

8j8f

EMDB-36068, PDB-8j8f:
Monkeypox virus DNA replication holoenzyme F8, A22 and E4 in complex with a DNA duplex and dCTP
Method: EM (single particle) / Resolution: 2.98 Å

36069

8j8g

EMDB-36069, PDB-8j8g:
Monkeypox virus DNA replication holoenzyme F8, A22 and E4 in complex with a DNA duplex and cidofovir diphosphate
Method: EM (single particle) / Resolution: 2.79 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-DCP:
2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE / Deoxycytidine triphosphate


ChemComp, No image

ChemComp-TXJ:
Unknown entry

Source
  • monkeypox virus
  • dna molecule (others)
KeywordsVIRAL PROTEIN / Monkeypox virus / DNA replication holoenzyme / DNA replication machinery / DNA polymerase / B-family DNA polymerase / uracil-DNA glycosylase / MPXV / orthopoxvirus / poxviridae / DNA processivity factor / DNA / CDVpp / cidofovir diphosphate

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