ArticlePLoS pathogens2014
Crystal structure of the vaccinia virus DNA polymerase holoenzyme subunit D4 in complex with the A20 N-terminal domain.
Article in PLoS pathogens, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19 citing papers in PubMed, 31 citations in OpenAlex.
- Structure and flexibility of the DNA polymerase holoenzyme of vaccinia virus.PLoS pathogens · 2024Article
- Structural insight into the assembly and working mechanism of helicase-primase D5 from Mpox virus.Nature structural & molecular biology · 2024Article
- Correlated Target Search by Vaccinia Virus Uracil-DNA Glycosylase, a DNA Repair Enzyme and a Processivity Factor of Viral Replication Machinery.International journal of molecular sciences · 2023Article
- Article
- Structural basis for the assembly of the DNA polymerase holoenzyme from a monkeypox virus variant.Science advances · 2023Article
- A small molecule that targets the processivity factor of molluscum contagiosum virus has therapeutic potential.Antiviral research · 2023Article
- Mutations in the monkeypox virus replication complex: Potential contributing factors to the 2022 outbreak.Journal of autoimmunity · 2022Article
- Inhibitors of DNA Glycosylases as Prospective Drugs.International journal of molecular sciences · 2020Review
- Punctuated Evolution of Myxoma Virus: Rapid and Disjunct Evolution of a Recent Viral Lineage in Australia.Journal of virology · 2019Article
- The French Armed Forces Virology Unit: A Chronological Record of Ongoing Research on Orthopoxvirus.Viruses · 2017Review
- The vaccinia virus DNA polymerase structure provides insights into the mode of processivity factor binding.Nature communications · 2017Article
- The vaccinia virus DNA polymerase and its processivity factor.Virus research · 2017Review
- A Conserved Tripeptide Sequence at the C Terminus of the Poxvirus DNA Processivity Factor D4 Is Essential for Protein Integrity and Function.The Journal of biological chemistry · 2016Article
- Poxvirus uracil-DNA glycosylase-An unusual member of the family I uracil-DNA glycosylases.Protein science : a publication of the Protein Society · 2016Review
- Structural analysis of point mutations at the Vaccinia virus A20/D4 interface.Acta crystallographica. Section F, Structural biology communications · 2016Article
- Crystal Structure of the Vaccinia Virus Uracil-DNA Glycosylase in Complex with DNA.The Journal of biological chemistry · 2015Article
- Binding of undamaged double stranded DNA to vaccinia virus uracil-DNA Glycosylase.BMC structural biology · 2015Article
- A novel target and approach for identifying antivirals against molluscum contagiosum virus.Antimicrobial agents and chemotherapy · 2014Article
- Uracil-DNA glycosylases-structural and functional perspectives on an essential family of DNA repair enzymes.Protein science : a publication of the Protein Society · 2014Review
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Vaccinia virus polymerase holoenzyme is composed of the DNA polymerase E9, the uracil-DNA glycosylase D4 and A20, a protein with no known enzymatic activity. The D4/A20 heterodimer is the DNA polymerase co-factor whose function is essential for processive DNA synthesis. Genetic and biochemical data have established that residues located in the N-terminus of A20 are critical for binding to D4. However, no information regarding the residues of D4 involved in A20 binding is yet available. We expressed and purified the complex formed by D4 and the first 50 amino acids of A20 (D4/A20₁₋₅₀). We showed that whereas D4 forms homodimers in solution when expressed alone, D4/A20₁₋₅₀ clearly behaves as a heterodimer. The crystal structure of D4/A20₁₋₅₀ solved at 1.85 Å resolution reveals that the D4/A20 interface (including residues 167 to 180 and 191 to 206 of D4) partially overlaps the previously described D4/D4 dimer interface. A20₁₋₅₀ binding to D4 is mediated by an α-helical domain with important leucine residues located at the very N-terminal end of A20 and a second stretch of residues containing Trp43 involved in stacking interactions with Arg167 and Pro173 of D4. Point mutations of the latter residues disturb D4/A20₁₋₅₀ formation and reduce significantly thermal stability of the complex. Interestingly, small molecule docking with anti-poxvirus inhibitors selected to interfere with D4/A20 binding could reproduce several key features of the D4/A20₁₋₅₀ interaction. Finally, we propose a model of D4/A20₁₋₅₀ in complex with DNA and discuss a number of mutants described in the literature, which affect DNA synthesis. Overall, our data give new insights into the assembly of the poxvirus DNA polymerase cofactor and may be useful for the design and rational improvement of antivirals targeting the D4/A20 interface.
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