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Human abh3 structure and key residues for oxidative demethylation to reverse DNA/rna damage

Academic Article
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Overview

authors

  • Sundheim, O.
  • Vagbo, C. B.
  • Bjoras, M.
  • Sousa, M. M. L.
  • Talstad, V.
  • Aas, P. A.
  • Drablos, F.
  • Krokan, H. E.
  • Tainer, John
  • Slupphaug, G.

publication date

  • July 2006

journal

  • EMBO Journal  Journal

abstract

  • Methylating agents are ubiquitous in the environment, and central in cancer therapy. The 1-methyladenine and 3-methylcytosine lesions in DNA/RNA contribute to the cytotoxicity of such agents. These lesions are directly reversed by ABH3 (hABH3) in humans and AlkB in Escherichia coli. Here, we report the structure of the hABH3 catalytic core in complex with iron and 2-oxoglutarate (2OG) at 1.5 A resolution and analyse key site-directed mutants. The hABH3 structure reveals the beta-strand jelly-roll fold that coordinates a catalytically active iron centre by a conserved His1-X-Asp/Glu-X(n)-His2 motif. This experimentally establishes hABH3 as a structural member of the Fe(II)/2OG-dependent dioxygenase superfamily, which couples substrate oxidation to conversion of 2OG into succinate and CO2. A positively charged DNA/RNA binding groove indicates a distinct nucleic acid binding conformation different from that predicted in the AlkB structure with three nucleotides. These results uncover previously unassigned key catalytic residues, identify a flexible hairpin involved in nucleotide flipping and ss/ds-DNA discrimination, and reveal self-hydroxylation of an active site leucine that may protect against uncoupled generation of dangerous oxygen radicals.

subject areas

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Catalytic Domain
  • Crystallography, X-Ray
  • DNA Damage
  • DNA Methylation
  • DNA Repair
  • DNA Repair Enzymes
  • DNA-Binding Proteins
  • Dioxygenases
  • Humans
  • Ketoglutaric Acids
  • Mixed Function Oxygenases
  • Molecular Sequence Data
  • Oxidation-Reduction
  • RNA
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Research

keywords

  • DNA repair
  • alkylation
  • crystal structure
  • hABH3
  • oxidative demethylation
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Identity

PubMed Central ID

  • PMC1523172

International Standard Serial Number (ISSN)

  • 0261-4189

Digital Object Identifier (DOI)

  • 10.1038/sj.emboj.7601219

PubMed ID

  • 16858410
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Additional Document Info

start page

  • 3389

end page

  • 3397

volume

  • 25

issue

  • 14

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