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DNA binding and nucleotide flipping by the human DNA repair protein agt

Academic Article
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Overview

authors

  • Daniels, Douglas
  • Woo, T. T.
  • Luu, K. X.
  • Noll, D. M.
  • Clarke, N. D.
  • Pegg, A. E.
  • Tainer, John

publication date

  • August 2004

journal

  • Nature Structural & Molecular Biology  Journal

abstract

  • O(6)-alkylguanine-DNA alkyltransferase (AGT), or O(6)-methylguanine-DNA methyltransferase (MGMT), prevents mutations and apoptosis resulting from alkylation damage to guanines. AGT irreversibly transfers the alkyl lesion to an active site cysteine in a stoichiometric, direct damage reversal pathway. AGT expression therefore elicits tumor resistance to alkylating chemotherapies, and AGT inhibitors are in clinical trials. We report here structures of human AGT in complex with double-stranded DNA containing the biological substrate O(6)-methylguanine or crosslinked to the mechanistic inhibitor N(1),O(6)-ethanoxanthosine. The prototypical DNA major groove-binding helix-turn-helix (HTH) motif mediates unprecedented minor groove DNA binding. This binding architecture has advantages for DNA repair and nucleotide flipping, and provides a paradigm for HTH interactions in sequence-independent DNA-binding proteins like RecQ and BRCA2. Structural and biochemical results further support an unpredicted role for Tyr114 in nucleotide flipping through phosphate rotation and an efficient kinetic mechanism for locating alkylated bases.

subject areas

  • Amino Acid Motifs
  • BRCA2 Protein
  • Binding Sites
  • Biotin
  • Catalysis
  • Crystallography, X-Ray
  • DNA
  • DNA Damage
  • DNA Repair
  • DNA, Single-Stranded
  • Escherichia coli
  • Guanine
  • Humans
  • Hydrogen Bonding
  • Models, Chemical
  • Models, Molecular
  • O(6)-Methylguanine-DNA Methyltransferase
  • Protein Binding
  • Ribonucleosides
  • Substrate Specificity
  • Tyrosine
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Identity

International Standard Serial Number (ISSN)

  • 1545-9985

Digital Object Identifier (DOI)

  • 10.1038/nsmb791

PubMed ID

  • 15221026
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Additional Document Info

start page

  • 714

end page

  • 720

volume

  • 11

issue

  • 8

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