Song Kun, Liu Xinyi, Huang Wenkang, Lu Shaoyong, Shen Qiancheng, Zhang Lu, Zhang Jian
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University, School of Medicine , Shanghai, 200025, China.
J Chem Inf Model. 2017 Sep 25;57(9):2358-2363. doi: 10.1021/acs.jcim.7b00014. Epub 2017 Aug 31.
Allosteric regulation induced by modulators binding to different, often distant, allosteric sites allows for exquisite control of protein functional activity. The structural diversity of allosteric sites endows allosteric modulators with high selectivity and low toxicity. Targeting allosteric sites, a novel tactic in drug discovery, has garnered much attention in the scientific community, and the identification of allosteric sites has become an important component of the development of allosteric drugs. Here we present AllositePro, a method which predicts allosteric sites in proteins by combining pocket features with perturbation analysis. The performance of AllositePro is superior to that of the other currently available methods. Using AllositePro, we predicted a novel allosteric site in cyclin-dependent kinase 2 (CDK2) and validated it by site-directed mutagenesis assay. Thus, the AllositePro method provides an effective way to identify allosteric sites and could be a useful strategy for allosteric drug discovery.
调节剂与不同的、通常相距较远的变构位点结合所诱导的变构调节，能够实现对蛋白质功能活性的精确控制。变构位点的结构多样性赋予变构调节剂高选择性和低毒性。靶向变构位点作为药物发现中的一种新策略，已在科学界引起广泛关注，变构位点的识别已成为变构药物开发的重要组成部分。在此，我们介绍AllositePro，这是一种通过结合口袋特征与扰动分析来预测蛋白质变构位点的方法。AllositePro的性能优于目前其他可用方法。利用AllositePro，我们在细胞周期蛋白依赖性激酶2（CDK2）中预测了一个新的变构位点，并通过定点诱变实验进行了验证。因此，AllositePro方法为识别变构位点提供了一种有效途径，可能成为变构药物发现的有用策略。
