Rational design of the survivin/CDK4 complex by combining protein–protein docking and molecular dynamics simulations

Abstract

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.

Alsterpaullone, a Cyclin-Dependent Kinase Inhibitor, Mediated Toxicity in HeLa Cells through Apoptosis-Inducing Effect

“…In this study, the results demonstrated the roles of apoptotic proteins in inhibition of alsterpaullone on HeLa cells. Mcl-1 is a short-lived protein because the PEST sequences present with the Bcl-2 family member, and it is an important anti-apoptotic protein [13, 14]. In the current study, we found that Mcl-1 protein was rapidly down-regulated and even undetectable as early as 2 h in HeLa cells.…”

Apoptosis induction of colorectal cancer cells HTL-9 in vitro by the transformed products of soybean isoflavones by Ganoderma lucidum

“…Therefore, activation of p53 can induce cell apoptosis by down-regulating the glucose metabolism level (Liu et al, 2015). In addition, Survivin is a newly discovered member of inhibitors of apoptosis proteins (IAPs) family, and can inhibit cell apoptosis mainly through inhibition of the activity of the caspase family (Selent et al, 2013). In this study, with TSI treatment, the relative expression of NF-κB was approximately 0.53 times that of the control, the mRNA expression of p53 was significantly increased, while the expression of Survivin was significantly decreased.…”

Drug Discovery and Molecular Dynamics: Methods, Applications and Perspective Beyond the Second Timescale

“…Selent et al also studied protein-protein binding by producing short MD simulations of 20 ns to refine a predicted complex between survivin/CDK4 [31].…”