Crystal structure of the PHF8 Jumonji domain, an Nepsilon-methyl lysine demethylase.
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.
Yue
Wyatt W
WW
Structural Genomics Consortium, University of Oxford, Headington, United Kingdom.
Hozjan
Viktorija
V
Ge
Wei
W
Loenarz
Christoph
C
Cooper
Christopher D O
CD
Schofield
Christopher J
CJ
Kavanagh
Kathryn L
KL
Oppermann
Udo
U
McDonough
Michael A
MA
D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D018360:Crystallography, X-Ray; D056466:Histone Demethylases; D006801:Humans; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000737:chemistry / Q000378:metabolism; D008239:Lysine / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D007656:Ketoglutaric Acids; D014157:Transcription Factors; D007501:Iron; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C511934:PHF8 protein, human; D008239:Lysine