Our research focuses on the structural biology of proteins involved in signal transduction (STATs, cytokines, hepatocyte growth factor) and regulation of gene expression (STATs and Nus proteins). We have also collaborated on a novel antiviral entry inhibitory protein, scytovirin. We approach our studies through elucidation of three-dimensional (3D) solution structure and dynamics of proteins and complexes, involving protein-protein, protein-nucleic, and protein-carbohydrate 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. 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 has developed new approaches to tagging macromolecules with paramagnetic centers and obtaining unique structural information about intermolecular interactions and structures of multi-component complexes. In this reporting period, our research has involved the transcription antiterminaton proteins NusB (from E.coli and Aquifex aeolicus) and NusE, the N-terminal domains of all members of the STAT transcription factor family, and the potent antiviral protein Scytovirin. Preliminary work is underway on systems related to protein degradation and the ubiquitination pathway, particularly the endoplasmic reticulum associated degradation (ERAD). We have determined the high-resolution structures [4] and investigated backbone dynamics and complexes of these proteins with their respective ligands or receptors. We continue to develop a cytokine receptor involved in high-grade gliomas, and we are examining the binding of cytokine to this receptor fragment.
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