Structure of vaccinia virus thymidine kinase in complex with dTTP: insights for drug design
Background: Development 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 strategi...
| Main Authors: | , , , , |
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| Format: | Journal article |
| Language: | English |
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BioMed Central
2006
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| Subjects: |
| _version_ | 1797060657652170752 |
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| author | El Omari, K Solaroli, N Karlsson, A Balzarini, J Stammers, D |
| author_facet | El Omari, K Solaroli, N Karlsson, A Balzarini, J Stammers, D |
| author_sort | El Omari, K |
| collection | OXFORD |
| description | Background: Development 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. Results: In 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. Conclusion: The 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. |
| first_indexed | 2024-03-06T20:20:12Z |
| format | Journal article |
| id | oxford-uuid:2d8b11cf-bfa8-47aa-aa61-17c44b8cdd66 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:20:12Z |
| publishDate | 2006 |
| publisher | BioMed Central |
| record_format | dspace |
| spelling | oxford-uuid:2d8b11cf-bfa8-47aa-aa61-17c44b8cdd662022-03-26T12:43:36ZStructure of vaccinia virus thymidine kinase in complex with dTTP: insights for drug designJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2d8b11cf-bfa8-47aa-aa61-17c44b8cdd66Biology (medical sciences)EnglishOxford University Research Archive - ValetBioMed Central2006El Omari, KSolaroli, NKarlsson, ABalzarini, JStammers, DBackground: Development 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. Results: In 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. Conclusion: The 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. |
| spellingShingle | Biology (medical sciences) El Omari, K Solaroli, N Karlsson, A Balzarini, J Stammers, D Structure of vaccinia virus thymidine kinase in complex with dTTP: insights for drug design |
| title | Structure of vaccinia virus thymidine kinase in complex with dTTP: insights for drug design |
| title_full | Structure of vaccinia virus thymidine kinase in complex with dTTP: insights for drug design |
| title_fullStr | Structure of vaccinia virus thymidine kinase in complex with dTTP: insights for drug design |
| title_full_unstemmed | Structure of vaccinia virus thymidine kinase in complex with dTTP: insights for drug design |
| title_short | Structure of vaccinia virus thymidine kinase in complex with dTTP: insights for drug design |
| title_sort | structure of vaccinia virus thymidine kinase in complex with dttp insights for drug design |
| topic | Biology (medical sciences) |
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