TY - JOUR
T1 - Crystal structure of the PHF8 Jumonji domain, an Nε-methyl lysine demethylase
AU - Yue, Wyatt W.
AU - Hozjan, Viktorija
AU - Ge, Wei
AU - Loenarz, Christoph
AU - Cooper, Christopher D O
AU - Schofield, Christopher J.
AU - Kavanagh, Kathryn L.
AU - Oppermann, Udo
AU - McDonough, Michael A.
PY - 2010/2
Y1 - 2010/2
N2 - Crystallographic analysis of the catalytic domain of PHD finger protein 8 (PHF8), an Nε-methyl lysine histone demethylase associated with mental retardation and cleft lip/palate, reveals a double-stranded β-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 Nε-methyl lysine demethylase subfamilies.
AB - Crystallographic analysis of the catalytic domain of PHD finger protein 8 (PHF8), an Nε-methyl lysine histone demethylase associated with mental retardation and cleft lip/palate, reveals a double-stranded β-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 Nε-methyl lysine demethylase subfamilies.
KW - 2-Oxoglutarate oxygenase
KW - Epigenetic modification
KW - Histone lysine demethylase
KW - JmjC
KW - Transcriptional regulation
UR - http://www.scopus.com/inward/record.url?scp=77649270417&partnerID=8YFLogxK
UR - http://febs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)1873-3468/
U2 - 10.1016/j.febslet.2009.12.055
DO - 10.1016/j.febslet.2009.12.055
M3 - Article
C2 - 20067792
AN - SCOPUS:77649270417
VL - 584
SP - 825
EP - 830
JO - FEBS Letters
JF - FEBS Letters
SN - 0014-5793
IS - 4
ER -