Full-length inhibitor protein is the most effective to perturb human dUTPase activity
Abstract It has been demonstrated recently that knockout of the dUTPase enzyme leads to early embryonic lethality in mice. However, to explore the physiological processes arising upon the lack of dUTPase an effective and selective enzyme inhibitor is much needed. A highly specific and strong binding...
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Nature Portfolio
2025-02-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-86131-7 |
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| author | Bianka Kőhegyi Zoé S. Tóth Enikő Gál Máté Laczkovich András Benedek Beáta G. Vértessy Kinga Nyíri |
| author_facet | Bianka Kőhegyi Zoé S. Tóth Enikő Gál Máté Laczkovich András Benedek Beáta G. Vértessy Kinga Nyíri |
| author_sort | Bianka Kőhegyi |
| collection | DOAJ |
| description | Abstract It has been demonstrated recently that knockout of the dUTPase enzyme leads to early embryonic lethality in mice. However, to explore the physiological processes arising upon the lack of dUTPase an effective and selective enzyme inhibitor is much needed. A highly specific and strong binding proteinaceous human dUTPase inhibitor described by us recently was a promising starting point to develop a molecular tool to study temporal and conditional dUTPase inhibition in cellulo. Towards this end we determined the 3D crystal structure of the crystallizable amino terminal domain of inhibitor protein, named StlNT in complex with the human dUTPase and designed several point mutants based on the structure to improve the inhibition effectivity. The effect of StlNT and a peptide derived from the full-length inhibitor on the activity of the human dUTPase was also tested. We showed that the C-terminal part of the Stl protein omitted from the crystal structure has an important role in the enzyme inhibition as the full-length Stl is needed to exert maximal inhibition on the human dUTPase. |
| format | Article |
| id | doaj-art-9dcadde637e2431db76cc70b1db870b6 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-9dcadde637e2431db76cc70b1db870b62025-02-09T12:30:33ZengNature PortfolioScientific Reports2045-23222025-02-0115111110.1038/s41598-025-86131-7Full-length inhibitor protein is the most effective to perturb human dUTPase activityBianka Kőhegyi0Zoé S. Tóth1Enikő Gál2Máté Laczkovich3András Benedek4Beáta G. Vértessy5Kinga Nyíri6Department of Applied Biotechnology and Food Science, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and EconomicsInstitute of Molecular Life Sciences, HUN-REN Research Centre for Natural SciencesDepartment of Applied Biotechnology and Food Science, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and EconomicsDepartment of Applied Biotechnology and Food Science, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and EconomicsDepartment of Applied Biotechnology and Food Science, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and EconomicsDepartment of Applied Biotechnology and Food Science, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and EconomicsDepartment of Applied Biotechnology and Food Science, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and EconomicsAbstract It has been demonstrated recently that knockout of the dUTPase enzyme leads to early embryonic lethality in mice. However, to explore the physiological processes arising upon the lack of dUTPase an effective and selective enzyme inhibitor is much needed. A highly specific and strong binding proteinaceous human dUTPase inhibitor described by us recently was a promising starting point to develop a molecular tool to study temporal and conditional dUTPase inhibition in cellulo. Towards this end we determined the 3D crystal structure of the crystallizable amino terminal domain of inhibitor protein, named StlNT in complex with the human dUTPase and designed several point mutants based on the structure to improve the inhibition effectivity. The effect of StlNT and a peptide derived from the full-length inhibitor on the activity of the human dUTPase was also tested. We showed that the C-terminal part of the Stl protein omitted from the crystal structure has an important role in the enzyme inhibition as the full-length Stl is needed to exert maximal inhibition on the human dUTPase.https://doi.org/10.1038/s41598-025-86131-7dUTPaseProteinaceous inhibitorPeptide inhibitorStructure based design |
| spellingShingle | Bianka Kőhegyi Zoé S. Tóth Enikő Gál Máté Laczkovich András Benedek Beáta G. Vértessy Kinga Nyíri Full-length inhibitor protein is the most effective to perturb human dUTPase activity Scientific Reports dUTPase Proteinaceous inhibitor Peptide inhibitor Structure based design |
| title | Full-length inhibitor protein is the most effective to perturb human dUTPase activity |
| title_full | Full-length inhibitor protein is the most effective to perturb human dUTPase activity |
| title_fullStr | Full-length inhibitor protein is the most effective to perturb human dUTPase activity |
| title_full_unstemmed | Full-length inhibitor protein is the most effective to perturb human dUTPase activity |
| title_short | Full-length inhibitor protein is the most effective to perturb human dUTPase activity |
| title_sort | full length inhibitor protein is the most effective to perturb human dutpase activity |
| topic | dUTPase Proteinaceous inhibitor Peptide inhibitor Structure based design |
| url | https://doi.org/10.1038/s41598-025-86131-7 |
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