Karasev D A, Veselovsky A V, Lagunin A A, Filimonov D A, Sobolev B N
Orekhovich Institute of Biomedical Chemistry, Russian Academy of Sciences, Moscow, 119121 Russia.
Pirogov Russian National Research Medical University, Moscow, 117997 Russia.
Mol Biol (Mosk). 2018 May-Jun;52(3):555-564. doi: 10.7868/S0026898418030199.
Identifying amino acid positions that determine the specific interaction of proteins with small molecule ligands, is required for search of pharmaceutical targets, drug design, and solution of other biotechnology problems. We studied applicability of an original method SPrOS (specificity projection on sequence) developed to recognize functionally significant positions in amino acid sequences. The method allows residues specific to functional subgroups to be determined within the protein family based on their local surroundings in amino acid sequences. The efficiency of the method has been estimated on the protein kinase family. The residues associated with the protein specificity to inhibitors have been predicted. The results have been verified using 3D structures of protein-ligand complexes. Three small molecule inhibitors have been tested. Residues predicted with SPrOS either in contacted the inhibitor or influenced the conformation of the ligand-binding area. Excluding close homologues from the studied set makes it possible to decrease the number of difficult to interpret positions. The expediency of this procedure was determined by the relationship between an inhibitory spectrum and phylogenic partition. Thus, the method efficiency has been confirmed by matching the prediction results with the protein 3D structures.
识别决定蛋白质与小分子配体特异性相互作用的氨基酸位置，对于寻找药物靶点、药物设计以及解决其他生物技术问题而言是必不可少的。我们研究了一种原创方法SPrOS（序列特异性投影）的适用性，该方法用于识别氨基酸序列中功能上重要的位置。该方法能够基于氨基酸序列中功能亚组的局部环境来确定蛋白质家族内特定于这些功能亚组的残基。已在蛋白激酶家族上评估了该方法的效率。预测了与蛋白质对抑制剂的特异性相关的残基。使用蛋白质 - 配体复合物的三维结构对结果进行了验证。测试了三种小分子抑制剂。用SPrOS预测的残基要么与抑制剂接触，要么影响配体结合区域的构象。从研究集中排除亲缘关系相近的同源物可以减少难以解释的位置数量。该步骤的合理性由抑制谱与系统发育划分之间的关系决定。因此，通过将预测结果与蛋白质三维结构进行匹配，证实了该方法的效率。
