靶向多梳组甲基赖氨酸读取蛋白 chromobox 同源物 7 (CBX7) 的染色质结构域拮抗剂。
Chromodomain antagonists that target the polycomb-group methyllysine reader protein chromobox homolog 7 (CBX7).
机构信息
Department of Chemistry, University of Victoria , P.O. Box 3065, Victoria, British Columbia, V8W 3V6, Canada.
出版信息
J Med Chem. 2014 Apr 10;57(7):2874-83. doi: 10.1021/jm401487x. Epub 2014 Mar 26.
We report here a peptide-driven approach to create first inhibitors of the chromobox homolog 7 (CBX7), a methyllysine reader protein. CBX7 uses its chromodomain to bind histone 3, lysine 27 trimethylated (H3K27me3), and this recognition event is implicated in silencing multiple tumor suppressors. Small trimethyllysine containing peptides were used as the basic scaffold from which potent ligands for disruption of CBX7-H3K27me3 complex were developed. Potency of ligands was determined by fluorescence polarization and/or isothermal titration calorimetry. Binding of one ligand was characterized in detail using 2D NMR and X-ray crystallography, revealing a structural motif unique among human CBX proteins. Inhibitors with a ∼200 nM potency for CBX7 binding and 10-fold/400-fold selectivity over related CBX8/CBX1 proteins were identified. These are the first reported inhibitors of any chromodomain.
我们在此报告了一种肽驱动的方法来创建第一个 CBX7（chromobox 同源物 7）的抑制剂，CBX7 是一种甲基赖氨酸读取蛋白。CBX7 使用其 chromodomain 来结合组蛋白 3、赖氨酸 27 三甲基化（H3K27me3），并且这种识别事件与沉默多种肿瘤抑制因子有关。含有小的三甲基赖氨酸的肽被用作基本支架，从这些支架中开发出了用于破坏 CBX7-H3K27me3 复合物的有效配体。通过荧光偏振和/或等温滴定量热法确定配体的效力。使用 2D NMR 和 X 射线晶体学详细表征了一种配体的结合情况，揭示了一种在人类 CBX 蛋白中独特的结构基序。鉴定出了对 CBX7 结合具有约 200 nM 效力的抑制剂，以及对相关 CBX8/CBX1 蛋白具有 10 倍/400 倍选择性的抑制剂。这些是首次报道的任何 chromodomain 的抑制剂。
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