NMR approaches for structural characterization of large proteins and protein complexes The overall goal of this research component is to develop methods for structural studies of large proteins and protein complexes using Nuclear Magnetic Resonance (NMR) spectroscopy. Solution NMR has become an important technique for studying structures and interactions of proteins. It can provide unique structural information for proteins that do not crystallize, answer questions about protein complexes where the significance of interactions is uncertain due to crystal contacts. While originally limited to only small proteins the technique has evolved and can now be used for structural studies of proteins beyond 50 kDa. However, the technique is still under development and major advances can be expected. We have made numerous technical innovations to the NMR methodology and propose to develop new techniques that will facilitate structural studies of large proteins and protein complexes, and increase the size limits of proteins that can be handled with solution NMR. We will apply the methods we develop to large systems that are involved in protein synthesis using internal ribosome entry sites (IRESs). This development of NMR technology in this project is central to this grant and will advance structural studies in the other projects. Thus, personnel of this component will be intensely involved in the other projects. We will pursue three specific aims: 1, Develop improved NMR experiments for characterizing large proteins and protein complexes 2: Characterize interactions of viral IRES elements with the first HEAT domain of elF4G and elF4A.
Developing the NMR technology for handling larger biological systems will provide new insights into dynamic biological mechanisms and will define new classes of drug targets such as protein-protein interactions and open new routes for curing human diseases.
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