1mu7
Crystal Structure of a Human Tyrosyl-DNA Phosphodiesterase (Tdp1)-Tungstate Complex
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OverviewOverview
Tyrosyl-DNA phosphodiesterase (Tdp1) is a DNA repair enzyme that catalyzes, the hydrolysis of a phosphodiester bond between a tyrosine residue and a, DNA 3'-phosphate. The only known example of such a linkage in eukaryotic, cells occurs normally as a transient link between a type IB topoisomerase, and DNA. Thus human Tdp1 is thought to be responsible for repairing, lesions that occur when topoisomerase I becomes stalled on the DNA in the, cell. Tdp1 has also been shown to remove glycolate from single-stranded, DNA containing a 3'-phosphoglycolate, suggesting a role for Tdp1 in repair, of free-radical mediated DNA double-strand breaks. We report the, three-dimensional structures of human Tdp1 bound to the phosphate, transition state analogs vanadate and tungstate. Each structure shows the, inhibitor covalently bound to His263, confirming that this residue is the, nucleophile in the first step of the catalytic reaction. Vanadate in the, Tdp1-vanadate structure has a trigonal bipyramidal geometry that mimics, the transition state for hydrolysis of a phosphodiester bond, while, Tdp1-tungstate displays unusual octahedral coordination. The presence of, low-occupancy tungstate molecules along the narrow groove of the substrate, binding cleft is suggestive evidence that this groove binds ssDNA. In both, cases, glycerol from the cryoprotectant solution became liganded to the, vanadate or tungstate inhibitor molecules in a bidentate 1,2-diol fashion., These structural models allow predictions to be made regarding the, specific binding mode of the substrate and the mechanism of catalysis.
About this StructureAbout this Structure
1MU7 is a Single protein structure of sequence from Homo sapiens with WO4 and GOL as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Insights into substrate binding and catalytic mechanism of human tyrosyl-DNA phosphodiesterase (Tdp1) from vanadate and tungstate-inhibited structures., Davies DR, Interthal H, Champoux JJ, Hol WG, J Mol Biol. 2002 Dec 13;324(5):917-32. PMID:12470949
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