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Crystal-structure and mutational analysis of human uracil-DNA glycosylase - structural basis for specificity and catalysis

Academic Article
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Overview

authors

  • Mol, C. D.
  • Arvai, A. S.
  • Slupphaug, G.
  • Kavli, B.
  • Alseth, I.
  • Krokan, H. E.
  • Tainer, John

publication date

  • March 1995

journal

  • Cell  Journal

abstract

  • Crystal structures of the DNA repair enzyme human uracil-DNA glycosylase (UDG), combined with mutational analysis, reveal the structural basis for the specificity of the enzyme. Within the classic alpha/beta fold of UDG, sequence-conserved residues form a positively charged, active-site groove the width of duplex DNA, at the C-terminal edge of the central four-stranded parallel beta sheet. In the UDG-6-aminouracil complex, uracil binds at the base of the groove within a rigid preformed pocket that confers selectivity for uracil over other bases by shape complementary and by main chain and Asn-204 side chain hydrogen bonds. Main chain nitrogen atoms are positioned to stabilize the oxyanion intermediate generated by His-268 acting via nucleophilic attack or general base mechanisms. Specific binding of uracil flipped out from a DNA duplex provides a structural mechanism for damaged base recognition.

subject areas

  • Amino Acid Sequence
  • Animals
  • Asparagine
  • Binding Sites
  • Catalysis
  • Cloning, Molecular
  • Crystallography, X-Ray
  • DNA Damage
  • DNA Glycosylases
  • DNA Mutational Analysis
  • DNA Repair
  • Escherichia coli
  • Histidine
  • Humans
  • Hydrogen Bonding
  • Models, Molecular
  • Molecular Sequence Data
  • N-Glycosyl Hydrolases
  • Protein Biosynthesis
  • Protein Conformation
  • Protein Folding
  • Protein Structure, Secondary
  • Rabbits
  • Recombinant Proteins
  • Reticulocytes
  • Substrate Specificity
  • Uracil-DNA Glycosidase
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Identity

International Standard Serial Number (ISSN)

  • 0092-8674

Digital Object Identifier (DOI)

  • 10.1016/0092-8674(95)90290-2

PubMed ID

  • 7697717
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Additional Document Info

start page

  • 869

end page

  • 878

volume

  • 80

issue

  • 6

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