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

Abstract

Cyclin-dependent protein kinase regulatory subunit 1 (Cks1) is involved in cell cycle progression through interactions with cyclin-dependent kinases (CDK) and ubiquitination of cyclin-dependent kinase inhibitors (CKI) . Dysfunction of CDK dependent associations can affect the entrance of a cell into mitosis, particularly the G1-S phase transition . Abnormal assistance from Cks1 with the multiprotein complex SCF (Skp2) in the ubiquitination of CDKN1B (p27 Kip1 ) can disrupt the mitotic regulatory protein levels escalating to cancer development . In this study, we use computational methods to investigate interactions in three different complexes sharing Cks1 in order to create a targeted pharmaceutical solution that will assist in regulation . Our analysis is performed using the crystal structure of Cks1 in three complexes to include involvement between one ubiquitin ligase and two CDKs . The assessment is based on the intermolecular electrostatic interactions, such as hydrogen bonds and charge-charge interactions . We observe that charge and hydrogen bonding plays a significant role in the stability between Cks1 and adjacent proteins in each complex. Due to large binding interfaces and varied distribution of charge across the main contact regions, we decided that a condensed pocket on Cks1 that interacts with phosphorylated p27 Kip1 should be selected for further in-depth examination .