Structural Bioinformatics Study of Cyclin-dependent Kinases Complexed with Inhibitors

Cell cycle progression is tightly controlled by the activity of cyclin-dependent kinases (CDKs) [31]. CDKs are inactive as monomers, and activation requires binding to cyclins, a diverse family of proteins whose levels oscillate during the cell cycle, and phosphorylation by CDK-activating kinase (CAK) on a specific threonine residue [19]. In addition to the positive regulatory role of cyclins and CAK, many negative regulatory proteins (CDK inhibitors, CKIs) have been discovered [34]. Since deregulation of cyclins and/or alteration or absence of CKIs have been associated with many cancers, there is strong interest in CDKs inhibitors that could play an important role in the discovery of a new family of antitumor agents [17]. CDKs also play a role in apoptosis (CDK2), in neuronal cells (CDK5) and in the control of transcription (CDK7, 8, 9) [9,20]. CDK5 is unique in the sense that although it is widely expressed in many tissues and cells, the CDK5 kinase activity is restricted to neuronal cells [10]. This specificity for neuronal tissue is the result of the CDK5 activator proteins p35, p25, and p39. CDK5 is a multifunctional kinase that associates with other cell proteins to interact with the cytoskeleton and form supramolecular complexes. Recent investigations have revealed that most of the CDK5 in cells forms large multimeric complexes of high molecular weight, ranging from 60 to 670 kDa, in which it is associated with p25, p35, Abstract