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

Journal article

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.

Authors: Yue, W; Hozjan, V; Ge, W; Loenarz, C; Cooper, C

• Publication status: Published
• Journal: FEBS letters
• Volume: 584
• Issue: 4
• Pages: 825-830
• Publication date: 2010-02-01
• DOI: 10.1016/j.febslet.2009.12.055
• EISSN: 1873-3468
• ISSN: 0014-5793
• Language: English
• Keywords: Histone Demethylases; Protein Conformation; Iron; Binding Sites; Protein Structure, Tertiary; Jumonji Domain-Containing Histone Demethylases; Mutation; Crystallography, X-Ray; Humans; Transcription Factors; Amino Acid Sequence; Molecular Sequence Data; Ketoglutaric Acids; Models, Molecular; Sequence Homology, Amino Acid; Protein Binding; Lysine