Structural Genomics Consortium, University of Oxford, Headington, United Kingdom.
FEBS Lett. 2010 Feb 19;584(4):825-30. doi: 10.1016/j.febslet.2009.12.055. Epub 2010 Jan 12.
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.
PHD 手指蛋白 8 (PHF8) 的催化结构域的晶体学分析，该蛋白与智力迟钝和唇裂/腭裂相关，是一种 N(epsilon)-甲基赖氨酸组蛋白去甲基酶，揭示了一种具有保守 Fe(II)和共底物结合位点的双链β-螺旋折叠，这些结合位点是 2-氧戊二酸依赖性加氧酶的典型特征。PHF8 活性位点与 FBXL10/11 去甲基酶高度保守，后者也选择性地针对二-/单甲基化赖氨酸状态，但与 JMJD2 去甲基酶不同，后者选择性地针对三-/二甲基化状态。这些结果解释了临床上观察到的 F279S PHF8 变体缺乏活性的原因，并且它们将有助于鉴定针对特定 N(epsilon)-甲基赖氨酸去甲基酶亚家族的选择性抑制剂。
