Our research focuses on the structural biology of proteins involved in signal transduction (STATs, cytokines, hepatocyte growth factor, MDM2) and regulation of gene expression (STATs and Nus proteins). We approach our studies through elucidation of three-dimensional (3D) solution structure and dynamics of proteins and complexes, involving protein-protein and protein-nucleic interactions, as a means of understanding the mechanism of action for these systems. Our primary technique is nuclear magnetic resonance (NMR) spectroscopy, which is unique among biophysical methods in its ability to provide atomic-resolution information on such systems in solution. The primary targets of our efforts are proteins involved in the transmission of signals between and within cells and proteins controlling gene expression. By investigating the structural biology of these systems, our studies can provide insight into the complex regulation of cell replication, which is crucial to the development and proliferation of cancer. Determining 3D solution structures requires state-of-the-art capabilities in multidimensional, triple- and quadruple-resonance NMR spectroscopy and isotopic labeling of proteins and nucleic acids. We devote a part of our efforts to the development of improved NMR techniques and hardware, as well as protein engineering. Recent work in our laboratory includes the establishment of procedures for the preparation of triply labeled proteins (e.g., N15, C13, and H2) both in uniform patterns and with selective methyl protonation in an otherwise N/C/D background. In this reporting period, our research has involved the transcription antiterminator NusB, hepatocyte growth factor (HGF), the N-terminal domain of STAT4, and human interleukin-13. Preliminary work is underway on systems related to apoptosis. We have determined the high-resolution structures and investigated backbone dynamics and complexes of these proteins with their respective ligands or receptors. We have developed an expression system for a cytokine receptor involved in high-grade gliomas, and we are examining the binding of cytokine to this receptor fragment.
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