Determination of the Structural Mechanism of the CDK4-Cyclin D1-p27 Complex
Physical and Biological Sciences
Chemistry
Cyclin-dependent kinase 4 (CDK4) is an enzyme involved in the transition from G1 to S phase in the cell cycle. Its primary function is to phosphorylate and inactivate the retinoblastoma protein (Rb) whose role is to prevent premature transition into S phase1. CDK4 activity is regulated by both cyclin D1 and p27Kip1 (p27) and deregulation of this complex leads to overproliferation, a hallmark of many cancers. Targeting the CDK4-cyclin D1-p27 complex in cancer cells suppresses tumor growth. The success of Palbociclib, a drug the selectively binds and inhibits the activity of CDK4 and CDK6, as a cancer therapeutic has shown the importance of understanding the mechanism of this kinase. Currently, there is very limited structural information about this complex. The objective of this research project is to use x-ray crystallography to elucidate the structure of CDK4-cyclin D1-p27 and from the structural information determine the mechanism by which this complex is regulated.
