Journal
FEBS LETTERS
Volume 584, Issue 4, Pages 825-830Publisher
WILEY
DOI: 10.1016/j.febslet.2009.12.055
Keywords
2-Oxoglutarate oxygenase; Histone lysine demethylase; Epigenetic modification; Transcriptional regulation; JmjC
Funding
- Oxford NIHR BRU
- BBSRC
- Wellcome Trust
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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. (C) 2010 Published by Elsevier B. V. on behalf of the Federation of European Biochemical Societies.
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