Mechanism of allosteric signal integration in Src tyrosine kinase

State University New York Stony Brook, Stony Brook NY

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Abstract

DESCRIPTION (provided by applicant): Protein kinases, as key cellular pathway regulators, are frequently linked to disease and provide opportunities for therapeutic intervention. Due to their prevalence and importance, strict regulation of kinase activity is necessary to control essential cellular processes including the cell cycle, proliferation, differentiation, motility, an cell death or survival. Small molecule kinase inhibitors selected for their ability to target the kinase ATP-binding pocket have achieved clinical utility. However, the high sequence and structural conservation of the pocket found in the more than 500 human protein kinases has created a challenge to developing inhibitors specific for individual kinases. Many limitations in using these small molecule inhibitors derive from their cross-inhibition of other kinases unconnected to the targeted disease process. Part of the mechanism through which protein kinases achieve precise regulation, though, involves integration of many inter- and intramolecular signals via sites that are considerably less well conserved in sequence and function. These non-conserved mechanisms of regulation therefore provide the opportunity for more precise therapeutic targeting, for example, through the development of allosteric inhibitors based on high-affinity and high-specificity ligands. However, it is challenging to identify such allosteric sites in detai. Recently, my sponsor's laboratory identified a previously unknown allosteric network of amino acids that spans the length of the kinase and may thus facilitate integration of allosteric signals into the regulation of protein kinase catalytic domain activity. I propose to experimentally probe the allosteric network and identify ligands that stabilize a predicted allosteric pocket. The findings from this work will deepen our understanding of the fundamental regulatory mechanisms for this important class of drug targets and potentially open the way to the development of more specific therapeutics.