ArticleBMC structural biology2006
Structure of vaccinia virus thymidine kinase in complex with dTTP: insights for drug design.
Article in BMC structural biology, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 39 citations in OpenAlex.
- Intravenous oncolytic vaccinia expressing transgenes for enhanced safety, inhibition of shedding, imaging, and systemic cancer immunotherapy.Molecular therapy. Oncology · 2026Article
- Vaccinia Virus-A Swiss Army Knife Against Cancer.Cancers · 2025Review
- A new attenuated and highly immunogenic orthopoxvirus vaccine protects against mpox in mice and macaques.NPJ vaccines · 2025Article
- In Silico Studies of Potential Selective Inhibitors of Thymidylate Kinase fromPharmaceuticals (Basel, Switzerland) · 2021Article
- Engineering and Preclinical Evaluation of Western Reserve Oncolytic Vaccinia Virus Expressing A167Y Mutant Herpes Simplex Virus Thymidine Kinase.Biomedicines · 2020Article
- Engineering and Characterization of Oncolytic Vaccinia Virus Expressing Truncated Herpes Simplex Virus Thymidine Kinase.Cancers · 2020Article
- Alpha-Herpesvirus Thymidine Kinase Genes Mediate Viral Virulence and Are Potential Therapeutic Targets.Frontiers in microbiology · 2019Review
- Targeting Nucleotide Biosynthesis: A Strategy for Improving the Oncolytic Potential of DNA Viruses.Frontiers in oncology · 2017Review
- KAY-2-41, a novel nucleoside analogue inhibitor of orthopoxviruses in vitro and in vivo.Antimicrobial agents and chemotherapy · 2014Article
- N3-substituted thymidine bioconjugates for cancer therapy and imaging.Future medicinal chemistry · 2013Review
- Synthesis of N3-substituted carboranyl thymidine bioconjugates and their evaluation as substrates of recombinant human thymidine kinase 1.European journal of medicinal chemistry · 2013Article
- Orthopoxvirus targets for the development of new antiviral agents.Antiviral research · 2012Review
- Article
- Poxvirus proteomics and virus-host protein interactions.Microbiology and molecular biology reviews : MMBR · 2009Review
- Crystal structure of poxvirus thymidylate kinase: an unexpected dimerization has implications for antiviral therapy.Proceedings of the National Academy of Sciences of the United States of America · 2008Article
- Selective phosphorylation of antiviral drugs by vaccinia virus thymidine kinase.Antimicrobial agents and chemotherapy · 2007Article
Corrections and comments
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Authors and funding
5 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundDevelopment of countermeasures to bioterrorist threats such as those posed by the smallpox virus (variola), include vaccination and drug development. Selective activation of nucleoside analogues by virus-encoded thymidine (dThd) kinases (TK) represents one of the most successful strategies for antiviral chemotherapy as demonstrated for anti-herpes drugs. Vaccinia virus TK is a close orthologue of variola TK but also shares a relatively high sequence identity to human type 2 TK (hTK), thus achieving drug selectivity relative to the host enzyme is challenging.
resultsIn order to identify any differences compared to hTK that may be exploitable in drug design, we have determined the crystal structure of VVTK, in complex with thymidine 5'-triphosphate (dTTP). Although most of the active site residues are conserved between hTK and VVTK, we observe a difference in conformation of residues Asp-43 and Arg-45. The equivalent residues in hTK hydrogen bond to dTTP, whereas in subunit D of VVTK, Asp-43 and Arg-45 adopt a different conformation preventing interaction with this nucleotide. Asp-43 and Arg-45 are present in a flexible loop, which is disordered in subunits A, B and C. The observed difference in conformation and flexibility may also explain the ability of VVTK to phosphorylate (South)-methanocarbathymine whereas, in contrast, no substrate activity with hTK is reported for this compound.
conclusionThe difference in conformation for Asp-43 and Arg-45 could thus be used in drug design to generate VVTK/Variola TK-selective nucleoside analogue substrates and/or inhibitors that have lower affinity for hTK.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.