Browsing by Author "Li, Geoffrey"

Now showing 1 - 2 of 2
  • No Thumbnail Available
    Item
    Analysis of the kinetics of binding of Protein Kinase A Inhibitor alpha (PKIa) to cAMP-dependent protein kinase a catalytic subunit (PKA-C)
    (2020-04-17) Li, Geoffrey; Muretta, Joseph; Olivieri, Cristina; vegli001@umn.edu; Veglia, Gianluigi
    TR-FRET raw data used for the analysis of the binding kinetic for full-length protein kinase inhibitor (PKIa) to ATP-saturated cAMP-dependent protein kinase A (PKA-C). The experiments are part of a publication on eLIFE: "Multi-state Recognition Pathway of the Intrinsically Disordered Protein Kinase Inhibitor by Protein Kinase A", where we investigated the structural and kinetics changed that PKIa undergoes upon interaction with PKA-C
  • Thumbnail Image
    Item
    On the Role of Conformational Dynamics in Allostery and Cooperativity in Protein Kinase A
    (2017-02) Li, Geoffrey
    Protein kinases are a large class of enzymes that regulate a wide array of vital cellular processes. Their dysregulation has been associated with fatal diseases including cancer, cardiovascular, and metabolic diseases. Hence, they have been important drug targets for years. While an enormous wealth of information about the structure and functions of kinases is available to date, a comprehensive mechanism of allosteric regulation of activity remains elusive. This thesis aims to investigate the role of conformational dynamics in the allosteric regulation and binding cooperativity of kinases using the cAMP-dependent protein kinase (PKA) as a model system. In this work, we demonstrated how allostery in PKA is propagated by changes in the hydrogen bond network between residues. We showed that different nucleotides and inhibitors modulate the allosteric cooperativity of PKA to different extent. Using NMR spectroscopy, we established how ligands influence substrate binding affinity by altering the kinase’s conformational dynamics through suppression and formation of sparsely-populated high-energy states. The findings of this work provide a new paradigm for designing more effective therapeutic agents that can steer the conformational landscape of kinases to better fine-tune their activity and functions.