Standing
Undergraduate
Type of Proposal
Oral Presentation
Faculty
Faculty of Science
Proposal
Computational explanation of the ineffectiveness of kinase drugs in the clinic: Spy1 vs. CycA as activators of Cdk2 Daniel Meister, S. Maryamdokht Taimoory, Rosa-Maria Ferraiuolo, Lisa Porter, John Trant* Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON, N9B 3P4, J.Trant@uwindsor.ca The Speedy/RINGO family of proteins are cell cycle regulators that interact with cyclin-dependent kinases (Cdks) without the need for cyclin binding or phosphorylation. Upregulation of the human homolog, SPY1 has been recently implicated in the development of multi-drug resistant breast cancers. This protein binds to Cyclin dependent kinase 2 (CDK2), activating it without the need for phosphorylation, resulting in an always on state. Additionally, it prevents the inhibitory effects of tumor suppressor p27 and triggers p27 degradation. Normally CDK2 must interact with Cyclin A and requires phosphorylation to function. This interaction leads to the correct orientation required for the binding of ATP and subsequent phosphate transfer, which SPY1 can mimic without the need for phosphorylation, and thus cannot be deactivated. Several anticancer drug compounds have been designed to target the CDK2/CycA complex to shut down cell division, yet these have little to no effect on cancer cells with up-regulated SPY1. We are investigating the mechanism that prevents inhibition using a computational approach involving docking to examine the binding of an array of drugs to determine if their reduced effectiveness is due to decreased binding affinity by comparing to known CDK2/CycA inhibitors. The interactions were further probed in depth using quantum mechanical/molecular mechanics approach. Spy1 binding results in decreased size CDK2 binding pocket conformation, preventing drug binding, with most of the drugs having decreased binding affinity to CDK2/Sy1. Information obtained will then be utilized to create inhibitors capable of targeting the key residues in the CDK2/Spy1 complex. Also investigated is the effect of various Spy1 mutants and their effects on CDK2 or p27 binding to identify key residues responsible for these interactions.
Grand Challenges
Understanding Borders
Computational explanation of the ineffectiveness of kinase drugs in the clinic: Spy1 vs. CycA as activators of Cdk2
Computational explanation of the ineffectiveness of kinase drugs in the clinic: Spy1 vs. CycA as activators of Cdk2 Daniel Meister, S. Maryamdokht Taimoory, Rosa-Maria Ferraiuolo, Lisa Porter, John Trant* Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON, N9B 3P4, J.Trant@uwindsor.ca The Speedy/RINGO family of proteins are cell cycle regulators that interact with cyclin-dependent kinases (Cdks) without the need for cyclin binding or phosphorylation. Upregulation of the human homolog, SPY1 has been recently implicated in the development of multi-drug resistant breast cancers. This protein binds to Cyclin dependent kinase 2 (CDK2), activating it without the need for phosphorylation, resulting in an always on state. Additionally, it prevents the inhibitory effects of tumor suppressor p27 and triggers p27 degradation. Normally CDK2 must interact with Cyclin A and requires phosphorylation to function. This interaction leads to the correct orientation required for the binding of ATP and subsequent phosphate transfer, which SPY1 can mimic without the need for phosphorylation, and thus cannot be deactivated. Several anticancer drug compounds have been designed to target the CDK2/CycA complex to shut down cell division, yet these have little to no effect on cancer cells with up-regulated SPY1. We are investigating the mechanism that prevents inhibition using a computational approach involving docking to examine the binding of an array of drugs to determine if their reduced effectiveness is due to decreased binding affinity by comparing to known CDK2/CycA inhibitors. The interactions were further probed in depth using quantum mechanical/molecular mechanics approach. Spy1 binding results in decreased size CDK2 binding pocket conformation, preventing drug binding, with most of the drugs having decreased binding affinity to CDK2/Sy1. Information obtained will then be utilized to create inhibitors capable of targeting the key residues in the CDK2/Spy1 complex. Also investigated is the effect of various Spy1 mutants and their effects on CDK2 or p27 binding to identify key residues responsible for these interactions.