Structure and Modeling

总的目标是表征十个重要的骨架结构和配体结合位点， 膜蛋白药物靶点，使用与现有最佳方法相容的方法， 这些蛋白质的膜模拟环境。通过使用溶液和固态NMR 我们的目标是交叉验证双层和胶束的结构表征，并采取 这两种方法的优势。建模和计算工作将用于完善 利用所有的结构限制和我们的集体膜蛋白 生物物理学知识来彻底表征这些潜在的药物靶标。这些信息将提供 进一步深入了解其生物学功能的特点，在项目1和2。这些结构还将有助于 鉴定对项目2中的靶蛋白具有高亲和力的化合物。 本课题的研究主要有三个方面：1）溶液和固体样品的制备 NMR; 2）主链结构和部分侧链结构的结构表征和动力学; （3）对初始模型进行结构细化，以提取结构和功能含义。 该项目汇集了位于NHMFL的三个研究小组的技能和经验， 伯纳姆研究所和加州大学圣地亚哥分校，并与其他项目和科学核心的每一个完全整合， 节目事实上，如果没有其他计划项目的努力，这个项目就无法实施。 以最重要的蛋白质为目标，大大增强了该项目的意义。

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'