The overall goal is to characterize the backbone structure and ligand binding sites of ten important membrane protein pharmaceutical targets using methods that are compatible with the best available membrane mimetic environments for these proteins. By using both solution and solid state NMR spectroscopy we aim to cross-validate the structural characterizations in bilayers and micelles, and to take advantage of the strengths of both approaches. Modeling and computational efforts will be used to refine the molecular structures by taking advantage of all the structural restraints and our collective membrane protein biophysical knowledge to thoroughly characterize these potential drug targets. This information will provide further insights to their biological functions characterized in Projects 1 and 2. The structures will also aid in the identification of chemical compounds that have high affinity for the target proteins in Project 2. The research in this Project is described by three aims: 1) Sample preparation for solution and solid state NMR;2) Structural characterization of the backbone structure and partial side-chain structure and dynamics; and 3) structural refinement of initial models for drawing structural and functional implications. This project brings together the skills and experience of three research groups located at the NHMFL, the Burnham Institute, and UCSD, and is fully integrated with each of the other Projects and Scientific Cores of the Program. Indeed, this Project could not be performed without the other Program Project efforts. Targeting the most important proteins greatly enhances the significance of this Project'
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