The major goal of this study is to increase our understanding, in terms of structure and dynamics, of the molecular mechanisms that regulate protein function in cellular signal transduction. Signaling pathways comprise numerous protein-protein interactions, and an individual protein often functions in multiple associations. Correspondingly, conformational flexibility plays an important role in molecular recognition events of protein-protein association and in the control of protein tyrosine kinase activation. NMR and computational methods will be used in this project to investigate conformational equilibrium important for recognition of Syk and Src-family kinases, and for conformational activation of Src kinase. Syk and Src-family protein tyrosine kinases are essential in B-cell signaling. Both Src family kinases and Syk family kinases are associated with several disease states and in particular with cell transformation. Detailed understanding of molecular recognition of these proteins is important for designing inhibitors and potential therapeutic agents against these diseases. A combination of NMR experiment and molecular dynamics computation will be used to determine the structure of various SH2 complexes and obtain information on protein motion related to binding and Src activation. We seek to understand: how conformational flexibility in the unbound state plays a role in determining binding; whether the large conformational change induced by binding to an interdomain region of Syk is general to recognition of this multifunctional site of Syk; what underlies entropy/enthalpy compensation in SH2 binding of flexible ligands; and how intramolecular domain contacts effect Src conformational activation.
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