title: Structural analysis of the inhibition of Cdk4 and Cdk6 by p16(INK4a) through molecular dynamics simulations.
abstract: Cyclin-dependent kinases 4, 6 and 2 (Cdk4/6/2), are proteins that lead progression through the G1-S transition, a step strictly regulated in the process of cell proliferation. The p16(INK4a) tumor suppressor, whose expression is inhibited in a high number of cancers, binds to Cdk4/6 and inhibits phosphorylation of the retinoblastoma protein, forcing cells to remain in the G1 phase and therefore, arresting cell division. Accordingly, the design of small compounds mimicking the inhibition of p16(INK4a) appears to be a promising way to treat cancer. In order to get some insight into the key interactions governing recognition between different cyclin-dependent kinases and the p16(INK4a) tumor suppressor, the present work reports the results of molecular dynamics simulations of both, the Cdk6-p16(INK4a) complex and the Cdk4-p16(INK4a) complex, respectively at 300 K. Most of the key interactions observed, were already anticipated in the analysis of the crystal structure of Cdk6-p16(INK4a). However, a few different features found out from the analysis of these calculations provide a better understanding of the role of the T-loop conformation, a fragment of Cdks, and the way the ATP binding-site is distorted upon binding of p16(INK4a).
authors.affiliation: Department de Química Física, Universitat de Barcelona, Martí i Franquès, 1, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Villacañas
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Pérez
authors.forename: Jaime
authors.initials: J
authors.lastname: Rubio-Martínez
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002453:Cell Cycle; D002455:Cell Division; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000494:pharmacology*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins; D017386:Sequence Homology, Amino Acid; D013696:Temperature
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases