Subramanian Jyothi, Sharma Somesh, B-Rao Chandrika
Cheminformatics, Nicholas Piramal Research Centre, 1 Nirlon Complex, Off Western Express Highway, Goregaon(E), Mumbai-400063, India.
J Med Chem. 2006 Sep 7;49(18):5434-41. doi: 10.1021/jm060172s.
Protein kinases in general are known to be very flexible macromolecules. In this article, the conformational plasticity of the ATP binding site in cyclin dependent kinases is analyzed. Movement of the two lysine residues lining the ATP binding site are shown to play a major role in the conformational variability of the site. Linear models are developed to identify and quantify ligand properties that maximally influence the lysine side chain conformations. A few simple properties of the ligands are shown to account for more than 70% of the variation in the lysine conformations. The results are validated using test data and molecular simulation studies. Illustrative applications of the results of this analysis to finding the appropriate crystal structure for molecular docking and binding mode predictions of novel ligands are provided. This work provides a new approach to quantify ligand-induced conformational changes in the active sites of flexible proteins and to find the appropriate crystal structure for docking novel ligands.
一般来说，蛋白激酶是非常灵活的大分子。在本文中，分析了细胞周期蛋白依赖性激酶中ATP结合位点的构象可塑性。结果表明，位于ATP结合位点的两个赖氨酸残基的移动在该位点的构象变异性中起主要作用。开发了线性模型来识别和量化对赖氨酸侧链构象影响最大的配体性质。结果表明，配体的一些简单性质占赖氨酸构象变化的70%以上。使用测试数据和分子模拟研究对结果进行了验证。提供了该分析结果在为新型配体的分子对接和结合模式预测寻找合适晶体结构方面的说明性应用。这项工作提供了一种新方法，用于量化柔性蛋白活性位点中配体诱导的构象变化，并为对接新型配体寻找合适的晶体结构。
