8c8i
From Proteopedia
Human dUTPase in complex with a potent proteinaceous inhibitor (Stl)
Structural highlights
FunctionDUT_HUMAN This enzyme is involved in nucleotide metabolism: it produces dUMP, the immediate precursor of thymidine nucleotides and it decreases the intracellular concentration of dUTP so that uracil cannot be incorporated into DNA.[1] Publication Abstract from PubMedIt 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 Stl(NT) in complex with the human dUTPase and designed several point mutants based on the structure to improve the inhibition effectivity. The effect of Stl(NT) 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. Full-length inhibitor protein is the most effective to perturb human dUTPase activity.,Kohegyi B, Toth ZS, Gal E, Laczkovich M, Benedek A, Vertessy BG, Nyiri K Sci Rep. 2025 Feb 9;15(1):4836. doi: 10.1038/s41598-025-86131-7. PMID:39924564[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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