Structural model of human dUTPase in complex with a novel proteinaceous inhibitor
| Autor: | Judit Matejka, Antoni J. Borysik, Oliver Ozohanics, Kinga Nyíri, M.J. Harris, Károly Vékey, Dmitri I. Svergun, Gergely N. Nagy, Haydyn D. T. Mertens, Bianka Kőhegyi, Judit Szabó, Beáta G. Vértessy, Veronika Papp-Kádár, Borbála Tihanyi, Veronika Németh-Pongrácz |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Staphylococcus aureus Protein Conformation lcsh:Medicine Repressor Plasma protein binding Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Protein structure Bacterial Proteins X-Ray Diffraction Catalytic Domain Scattering Small Angle Humans Pyrophosphatases lcsh:Science chemistry.chemical_classification Multidisciplinary biology Functional analysis lcsh:R Active site Staphylococcal Infections Deoxyuridine 3. Good health Molecular Docking Simulation Repressor Proteins 030104 developmental biology Enzyme chemistry 030220 oncology & carcinogenesis biology.protein Biophysics lcsh:Q Protein Multimerization ddc:600 DNA Protein Binding |
| Zdroj: | Scientific Reports Scientific Reports, Vol 8, Iss 1, Pp 1-15 (2018) Scientific reports 8(1), 4326 (2018). doi:10.1038/s41598-018-22145-8 Nyíri, K, Mertens, H D T, Tihanyi, B, Nagy, G N, Kohegyi, B, Matejka, J, Harris, M J, Szabó, J E, Papp-Kádár, V, Németh-Pongrácz, V, Ozohanics, O, Vékey, K, Svergun, D I, Borysik, A J & Vértessy, B G 2018, ' Structural model of human dUTPase in complex with a novel proteinaceous inhibitor ', Scientific Reports, vol. 8, no. 1, 4326 . https://doi.org/10.1038/s41598-018-22145-8 |
| ISSN: | 2045-2322 |
| Popis: | Human deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase), essential for DNA integrity, acts as a survival factor for tumor cells and is a target for cancer chemotherapy. Here we report that the Staphylococcal repressor protein StlSaPIBov1 (Stl) forms strong complex with human dUTPase. Functional analysis reveals that this interaction results in significant reduction of both dUTPase enzymatic activity and DNA binding capability of Stl. We conducted structural studies to understand the mechanism of this mutual inhibition. Small-angle X-ray scattering (SAXS) complemented with hydrogen-deuterium exchange mass spectrometry (HDX-MS) data allowed us to obtain 3D structural models comprising a trimeric dUTPase complexed with separate Stl monomers. These models thus reveal that upon dUTPase-Stl complex formation the functional homodimer of Stl repressor dissociates, which abolishes the DNA binding ability of the protein. Active site forming dUTPase segments were directly identified to be involved in the dUTPase-Stl interaction by HDX-MS, explaining the loss of dUTPase activity upon complexation. Our results provide key novel structural insights that pave the way for further applications of the first potent proteinaceous inhibitor of human dUTPase. |
| Databáze: | OpenAIRE |
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