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FEBS Lett. 2007 Oct 2;581(24):4783-8. Epub 2007 Sep 12.

Active site closure facilitates juxtaposition of reactant atoms for initiation of catalysis by human dUTPase.

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  • 1Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Budapest, Hungary.


Human dUTPase, essential for DNA integrity, is an important survival factor for cancer cells. We determined the crystal structure of the enzyme:alpha,beta-imino-dUTP:Mg complex and performed equilibrium binding experiments in solution. Ordering of the C-terminus upon the active site induces close juxtaposition of the incoming nucleophile attacker water oxygen and the alpha-phosphorus of the substrate, decreasing their distance below the van der Waals limit. Complex interactions of the C-terminus with both substrate and product were observed via a specifically designed tryptophan sensor, suitable for further detailed kinetic and ligand binding studies. Results explain the key functional role of the C-terminus.

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