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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.

Original publication

DOI

10.1016/j.febslet.2009.12.055

Type

Journal article

Journal

FEBS Lett

Publication Date

19/02/2010

Volume

584

Pages

825 - 830

Keywords

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