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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.

Type

Journal article

Journal

FEBS letters

Publication Date

02/2010

Volume

584

Pages

825 - 830

Addresses

Structural Genomics Consortium, University of Oxford, Headington, United Kingdom.

Keywords

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