ArticleThe Journal of biological chemistry2011
Phosphonoformic acid inhibits viral replication by trapping the closed form of the DNA polymerase.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 54 citations in OpenAlex.
- Article
- Small Molecule Drugs Targeting Viral Polymerases.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Restructured membrane contacts rewire organelles for human cytomegalovirus infection.Nature communications · 2022Article
- Inhibition ofIUCrJ · 2022Article
- Poxviruses Bearing DNA Polymerase Mutations Show Complex Patterns of Cross-Resistance.Biomedicines · 2022Article
- A Well-Conserved Archaeal B-Family Polymerase Functions as an Extender in Translesion Synthesis.mBio · 2022Article
- Analysis of Novel Drug-Resistant Human Cytomegalovirus DNA Polymerase Mutations Reveals the Role of a DNA-Binding Loop in Phosphonoformic Acid Resistance.Frontiers in microbiology · 2022Article
- Impact of Amino Acid Substitutions in Region II and Helix K of Herpes Simplex Virus 1 and Human Cytomegalovirus DNA Polymerases on Resistance to Foscarnet.Antimicrobial agents and chemotherapy · 2021Article
- Structural understanding of non-nucleoside inhibition in an elongating herpesvirus polymerase.Nature communications · 2021Article
- Structure of New Binary and Ternary DNA Polymerase Complexes From Bacteriophage RB69.Frontiers in molecular biosciences · 2021Article
- Antiviral Drugs Against Herpesviruses.Advances in experimental medicine and biology · 2021Article
- Hypersusceptibility of Human Cytomegalovirus to Foscarnet Induced by Mutations in Helices K and P of the Viral DNA Polymerase.Antimicrobial agents and chemotherapy · 2020Article
- Conjugation of phosphonoacetic acid to nucleobase promotes a mechanism-based inhibition.Journal of enzyme inhibition and medicinal chemistry · 2018Article
- DNA synthesis from diphosphate substrates by DNA polymerases.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- The vaccinia virus DNA polymerase structure provides insights into the mode of processivity factor binding.Nature communications · 2017Article
- Remote Mutations Induce Functional Changes in Active Site Residues of Human DNA Polymerase β.Biochemistry · 2017Article
- Foscarnet resistance mutations mapping to atypical domains of the cytomegalovirus DNA polymerase gene.Antiviral research · 2017Article
- Distribution and effects of amino acid changes in drug-resistant α and β herpesviruses DNA polymerase.Nucleic acids research · 2016Review
- Molecular events during translocation and proofreading extracted from 200 static structures of DNA polymerase.Nucleic acids research · 2016Article
- Conformational States of HIV-1 Reverse Transcriptase for Nucleotide Incorporation vs Pyrophosphorolysis-Binding of Foscarnet.ACS chemical biology · 2016Article
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
Phosphonoformic acid (PFA, foscarnet) belongs to a class of antiviral drugs that inhibit the human cytomegalovirus DNA polymerase (UL54) by mimicking the pyrophosphate leaving group of the nucleotide transfer reaction. Difficulties expressing UL54 have hampered investigation of the precise structural requirements rendering inhibition by this drug. However, a previously engineered chimeric DNA polymerase, constructed by mutating the homologous polymerase from bacteriophage RB69 (gp43) to express several variable elements from UL54, can bypass this obstacle because of its favorable expression and acquired sensitivity to PFA (Tchesnokov, E. P., Obikhod, A., Schinazi, R. F., and Götte, M. (2008) J. Biol. Chem. 283, 34218-34228). Here, we compare two crystal structures that depict the chimeric DNA polymerase with and without PFA bound. PFA is visualized for the first time in the active site of a DNA polymerase, where interactions are resolved between the PP(i) mimic and two basic residues absolutely conserved in the fingers domain of family B polymerases. PFA also chelates metal ion B, the cation that contacts the triphosphate tail of the incoming nucleotide. These DNA complexes utilize a primer-template pair enzymatically chain-terminated by incorporation of acyclo-GMP, the phosphorylated form of the anti-herpes drug acyclovir. We postulate that the V478W mutation present in the chimera is critical in that it pushes the fingers domain to more readily adopt the closed conformation whether or not the drug is bound. The closed state of the fingers domain traps the variant polymerase in the untranslocated state and increases affinity for PFA. This finding provides a model for the mechanism of UL54 stalling by PFA.
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