Crystal structure of the PHF8 Jumonji domain, an Nepsilon-methyl lysine demethylase

FEBS Lett. 2010 Feb 19;584(4):825-30. doi: 10.1016/j.febslet.2009.12.055. Epub 2010 Jan 12.

Abstract

Crystallographic analysis of the catalytic domain of PHD finger protein 8 (PHF8), an N(epsilon)-methyl lysine histone demethylase associated with mental retardation and cleft lip/palate, reveals a double-stranded beta-helix fold with conserved Fe(II) and cosubstrate binding sites typical of the 2-oxoglutarate dependent oxygenases. The PHF8 active site is highly conserved with those of the FBXL10/11demethylases, which are also selective for the di-/mono-methylated lysine states, but differs from that of the JMJD2 demethylases which are selective for tri-/di-methylated states. The results rationalize the lack of activity for the clinically observed F279S PHF8 variant and they will help to identify inhibitors selective for specific N(epsilon)-methyl lysine demethylase subfamilies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites / genetics
  • Crystallography, X-Ray
  • Histone Demethylases
  • Humans
  • Iron / chemistry
  • Iron / metabolism
  • Jumonji Domain-Containing Histone Demethylases / chemistry
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Ketoglutaric Acids / chemistry
  • Ketoglutaric Acids / metabolism
  • Lysine / chemistry
  • Lysine / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary*
  • Sequence Homology, Amino Acid
  • Transcription Factors / chemistry*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Ketoglutaric Acids
  • Transcription Factors
  • Iron
  • Histone Demethylases
  • Jumonji Domain-Containing Histone Demethylases
  • PHF8 protein, human
  • Lysine