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Crystal structure of the PHF8 Jumonji domain, an N ε ‐methyl lysine demethylase
Author(s) -
Yue Wyatt W.,
Hozjan Viktorija,
Ge Wei,
Loenarz Christoph,
Cooper Christopher D.O.,
Schofield Christopher J.,
Kavanagh Kathryn L.,
Oppermann Udo,
McDonough Michael A.
Publication year - 2010
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2009.12.055
Subject(s) - demethylase , phd finger , lysine , chemistry , histone , histone h3 , stereochemistry , biochemistry , helix (gastropod) , crystallography , biology , gene , amino acid , zinc finger , transcription factor , ecology , snail
Crystallographic analysis of the catalytic domain of PHD finger protein 8 (PHF8), an N ε ‐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 N ε ‐methyl lysine demethylase subfamilies.