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A NUCLEOTIDE-FLIPPING MECHANISM FROM THE STRUCTURE OF HUMAN URACIL-DNA GLYCOSYLASE BOUND TO DNA

spinqualitylabelsall models 4skn, resolution 2.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4skn is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: URA, ORP Activity: Uridine nucleosidase, with EC number 3.2.2.3 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Introduction Glycosylase is an enzyme. Its main function is in Base Excision Repair(BER). Base Excision Repair is a DNA repair mechanism that fixes the most common type of DNA damage. BER removes and repairs damaged bases usually these are single-stranded DNA breaks. BER corrects DNA damage that results from small leisures that do not disrupt the double helix. Function Glycosylase does this by cleaving the glycosidic bond of the damaged nucleotide, leaving the Deoxyribose nucleotide with no base. The deoxyribose is then cleaved by AP endonuclease creating an AP site. The gap that is left is filled in through DNA Polymerase and DNA ligase. Uracil-DNA Glycosylase The structure of Glycosylase has a couple of different forms in terms of its general structure there is Adenine and Uracil Glycosylase. DNA Uracil-Glycosylase specifically looks for any Uracil in the double-stranded DNA. It looks for Uracil in dsDNA because uracil is only found in ssDNA. So if a Uracil is found in dsDNA then that means the strand has been damaged and needs repair. When Uracil-DNA Glycosylase finds the Uracil site it binds to it. The Active Site of Uracil Glycosylase; D145, Y147, F158, N204, H268, L272 is what binds to the double-stranded DNA with the damaged lesion. Then a nucleotide-flipping mechanism flips the site of repair out of the double helix. The dsDNA has a 10bp that contains a U G base pair mismatch. This is what allows the Uracil and Glycosylase interaction and flip the damaged site out of the double helix. When flipped out of the helix ARG 272 side chain takes its place in the minor groove since AP sites can be mutagenic. The Uracil is then replaced with a Thymine. This is because Uracil and Thymine have identical base pairing properties. Thymine happens to have greater resistance to photochemical mutations which is why we see it in dsDNA and not Uracil.