Structural Genomics Consortium, University of Toronto, MaRS Centre, 101 College Street, Toronto, Ontario, Canada.
J Chem Inf Model. 2010 Mar 22;50(3):358-67. doi: 10.1021/ci900427b.
A simple computational approach was developed to screen the Protein Data Bank (PDB) for putative pockets possessing a specific binding site chemistry and geometry. The method employs two commonly used 3D screening technologies, namely identification of cavities in protein structures and pharmacophore screening of chemical libraries. For each protein structure, a pocket finding algorithm is used to extract potential binding sites containing the correct types of residues, which are then stored in a large SDF-formatted virtual library; pharmacophore filters describing the desired binding site chemistry and geometry are then applied to screen this virtual library and identify pockets matching the specified structural chemistry. As an example, this approach was used to screen all human protein structures in the PDB and identify sites having chemistry similar to that of known methyl-lysine binding domains that recognize chromatin methylation marks. The selected genes include known readers of the histone code as well as novel binding pockets that may be involved in epigenetic signaling. Putative allosteric sites were identified on the structures of TP53BP1, L3MBTL3, CHEK1, KDM4A, and CREBBP.
开发了一种简单的计算方法，用于从蛋白质数据库 (PDB) 中筛选具有特定结合位点化学性质和几何形状的潜在口袋。该方法采用了两种常用的 3D 筛选技术，即识别蛋白质结构中的空腔和化学文库的药效团筛选。对于每个蛋白质结构，使用口袋发现算法提取含有正确类型残基的潜在结合位点，并将其存储在大型 SDF 格式的虚拟库中；然后应用描述所需结合位点化学性质和几何形状的药效团过滤器来筛选这个虚拟库并识别与指定结构化学相匹配的口袋。例如，该方法用于筛选 PDB 中的所有人类蛋白质结构，并识别具有与已知甲基-赖氨酸结合结构域相似化学性质的位点，这些结构域可以识别染色质甲基化标记。选定的基因包括组蛋白密码的已知阅读器以及可能参与表观遗传信号的新的结合口袋。在 TP53BP1、L3MBTL3、CHEK1、KDM4A 和 CREBBP 的结构上鉴定出了假定的别构位点。
