Identification of Targetable Surfaces of Cks1 for Development of New Cancer Therapeutics

Author(s): Winicki, Nolan; Harrison, Reed; Perry, Jefferson; Morikis, Dimitrios | Abstract: Cyclin-dependent protein kinase regulatory subunit 1 (Cks1) is involved in cell cycle progressionthrough interactions with cyclin-dependent kinases (CDK) and ubiquitination of cyclin-dependentkinase inhibitors (CKI). Dysfunction of CDK dependent associations can affect the entrance of acell into mitosis, particularly the G1-S phase transition. Abnormal assistance from Cks1 with themultiprotein complex SCF (Skp2) in the ubiquitination of CDKN1B (p27Kip1) can disrupt the mitoticregulatory protein levels escalating to cancer development. In this study, we use computationalmethods to investigate interactions in three different complexes sharing Cks1 in order to create atargeted pharmaceutical solution that will assist in regulation. Our analysis is performed using thecrystal structure of Cks1 in three complexes to include involvement between one ubiquitin ligaseand two CDKs. The assessment is based on the intermolecular electrostatic interactions, such ashydrogen bonds and charge-charge interactions. We observe that charge and hydrogen bonding playsa significant role in the stability between Cks1 and adjacent proteins in each complex. Due to largebinding interfaces and varied distribution of charge across the main contact regions, we decided thata condensed pocket on Cks1 that interacts with phosphorylated p27Kip1 should be selected for furtherin-depth examination.