Research Programme on Biomedical Informatics (GRIB), IMIM/Universitat Pompeu Fabra, Dr. Aiguader 88, 08003 Barcelona, Spain.
J Mol Model. 2013 Apr;19(4):1507-14. doi: 10.1007/s00894-012-1705-8. Epub 2012 Dec 21.
Survivin, the smallest inhibitor of apoptosis protein (IAP), is a valid target for cancer research. It mediates both the apoptosis pathway and the cell cycle and has been proposed to form a complex with the cyclin-dependent kinase protein CDK4. The resulting complex transports CDK4 from the cytosol to the nucleus, where CDK4 participates in cell division. Survivin has been recognized as a node protein that interacts with several partners; disruption of the formed complexes can lead to new anticancer compounds. We propose a rational model of the survivin/CDK4 complex that fulfills the experimental evidence and that can be used for structure-based design of inhibitors modifying its interface recognition. In particular, the suggested complex involves the alpha helical domain of survivin and resembles the mode of binding of survivin in the survivin/borealin X-ray structure. The proposed model has been obtained by combining protein-protein docking, fractal-based shape complementarity, electrostatics studies and extensive molecular dynamics simulations.
Survivin，凋亡抑制蛋白家族（IAPs）中最小的一员，是癌症研究的有效靶点。它既能介导细胞凋亡通路，又能调节细胞周期，而且与细胞周期蛋白依赖性激酶 CDK4 形成复合物。形成的复合物将 CDK4 从细胞质转运到细胞核，而 CDK4 参与细胞分裂。Survivin 被认为是一种节点蛋白，与多个伙伴相互作用；形成的复合物的破坏会导致新的抗癌化合物。我们提出了一个合理的 survivin/CDK4 复合物模型，该模型满足实验证据，可以用于基于结构的抑制剂设计，以修饰其界面识别。特别是，所提出的复合物涉及 survivin 的α螺旋结构域，类似于 survivin/borealin X 射线结构中 survivin 的结合模式。所提出的模型是通过结合蛋白质-蛋白质对接、分形形状互补、静电研究和广泛的分子动力学模拟获得的。
