Cabaye Alexandre, Nguyen Kong T, Liu Lihua, Pande Vineet, Schapira Matthieu
Structural Genomics Consortium, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
Discovery Sciences, Janssen Pharmaceutical Companies of Johnson and Johnson, Beerse, 2340, Belgium.
Proteins. 2015 Jul;83(7):1316-26. doi: 10.1002/prot.24830. Epub 2015 May 29.
Protein families involved in chromatin-templated events are emerging as novel target classes in oncology and other disease areas. The ability to discover selective inhibitors against chromatin factors depends on the presence of structural features that are unique to the targeted sites. To evaluate challenges and opportunities toward the development of selective inhibitors, we calculated all pair wise structural distances between 575 structures from the protein databank representing 163 unique binding pockets found in protein domains that write, read or erase post-translational modifications on histones, DNA, and RNA. We find that the structural similarity of binding sites does not always follow the sequence similarity of protein domains. Our analysis reveals increased risks of activity across target-class for compounds competing with the cofactor of protein arginine methyltransferases, lysine acetyltransferases, and sirtuins, while exploiting the conformational plasticity of a protein target is a path toward selective inhibition. The structural diversity landscape of the epigenetics pocketome can be explored via an open-access graphic user interface at thesgc.org/epigenetics_pocketome.
参与染色质模板化事件的蛋白质家族正成为肿瘤学和其他疾病领域的新型靶点类别。发现针对染色质因子的选择性抑制剂的能力取决于靶向位点所特有的结构特征的存在。为了评估开发选择性抑制剂所面临的挑战和机遇，我们计算了蛋白质数据库中575个结构之间的所有成对结构距离，这些结构代表了在组蛋白、DNA和RNA上写入、读取或擦除翻译后修饰的蛋白质结构域中发现的163个独特结合口袋。我们发现结合位点的结构相似性并不总是遵循蛋白质结构域的序列相似性。我们的分析揭示了与蛋白质精氨酸甲基转移酶、赖氨酸乙酰转移酶和沉默调节蛋白的辅因子竞争的化合物在跨靶点类别中产生活性的风险增加，而利用蛋白质靶点的构象可塑性是实现选择性抑制的一条途径。表观遗传口袋组的结构多样性景观可通过thesgc.org/epigenetics_pocketome上的开放获取图形用户界面进行探索。
