On the Role of Conformational Dynamics in Allostery and Cooperativity in Protein Kinase A
2017-02
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On the Role of Conformational Dynamics in Allostery and Cooperativity in Protein Kinase A
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2017-02
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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.
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University of Minnesota Ph.D. dissertation. February 2017. Major: Chemistry. Advisor: Gianluigi Veglia. 1 computer file (PDF); xi, 203 pages.
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Li, Geoffrey. (2017). On the Role of Conformational Dynamics in Allostery and Cooperativity in Protein Kinase A. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/195388.
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