Chen Hao, Zhao Yunjie, Li Haotian, Zhang Dongyan, Huang Yanzhao, Shen Qi, Van Duyne Rachel, Kashanchi Fatah, Zeng Chen, Liu Shiyong
Department of Physics, The George Washington University, Washington, D. C., United States of America.
Department of Physics, Huazhong University of Science and Technology, Wuhan, Hubei, China.
PLoS One. 2014 Oct 7;9(10):e109154. doi: 10.1371/journal.pone.0109154. eCollection 2014.
Most inhibitors of Cyclin-dependent kinase 2 (CDK2) target its ATP-binding pocket. It is difficult, however, to use this pocket to design very specific inhibitors because this catalytic pocket is highly conserved in the protein family of CDKs. Here we report some short peptides targeting a noncatalytic pocket near the interface of the CDK2/Cyclin complex. Docking and molecular dynamics simulations were used to select the peptides, and detailed dynamical network analysis revealed that these peptides weaken the complex formation via allosteric interactions. Our experiments showed that upon binding to the noncatalytic pocket, these peptides break the CDK2/Cyclin complex partially and diminish its kinase activity in vitro. The binding affinity of these peptides measured by Surface Plasmon Resonance can reach as low as 0.5 µM.
大多数细胞周期蛋白依赖性激酶2（CDK2）抑制剂靶向其ATP结合口袋。然而，利用这个口袋设计高度特异性的抑制剂很困难，因为这个催化口袋在CDK蛋白家族中高度保守。在这里，我们报道了一些靶向CDK2/细胞周期蛋白复合物界面附近非催化口袋的短肽。通过对接和分子动力学模拟来选择这些肽，详细的动力学网络分析表明，这些肽通过变构相互作用削弱复合物的形成。我们的实验表明，这些肽与非催化口袋结合后，会部分破坏CDK2/细胞周期蛋白复合物，并在体外降低其激酶活性。通过表面等离子体共振测量，这些肽的结合亲和力可低至0.5μM。
