Structure and Modeling

结构和建模

• 批准号: 7575459
• 负责人: TIMOTHY A CROSS
• 金额: $ 52.53万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-20 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7575459
• 关键词: Accounting; Advanced Development; Affinity; Amino Acids; Binding; Binding Sites; Biological; Biological Process; Chemicals; Computer Simulation; Data; Development; Drug Delivery Systems; Environment; Frequencies; Goals; Home environment; Image; Institutes; Knowledge; Laboratories; Ligand Binding; Lipid Bilayers; Membrane; Membrane Proteins; Methodology; Methods; Micelles; Modeling; Molecular Conformation; Molecular Structure; Mycobacterium tuberculosis; NMR Spectroscopy; Pharmacologic Substance; Preparation; Protein NMR Spectroscopy; Proteins; Research; Research Personnel; Sampling; Side; Site; Solutions; Structural Models; Structure; Technology; Testing; Vertebral column; Water; Work; design; experience; insight; instrument; instrumentation; magnetic field; mimetics; programs; protein expression; protein function; protein structure; restraint; skills; small molecule; solid state; solid state nuclear magnetic resonance; success

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'

总体目标是表征十个重要的主链结构和配体结合位点 使用与现有最佳方法兼容的方法来实现膜蛋白药物靶标 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 充分利用两种方法的优点。建模和计算工作将用于完善 利用所有结构限制和我们的集体膜蛋白来确定分子结构 生物物理知识来彻底表征这些潜在的药物靶点。该信息将提供 进一步了解项目 1 和项目 2 中表征的生物功能。这些结构还将有助于 鉴定与项目 2 中的目标蛋白具有高亲和力的化合物。 该项目的研究分为三个目标：1）溶液和固态样品制备 核磁共振； 2）主链结构和部分侧链结构及动力学的结构表征； 3）对初始模型进行结构细化，以绘制结构和功能含义。 该项目汇集了 NHMFL 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完全集成 该计划。事实上，如果没有其他计划项目的努力，这个项目就不可能完成。 针对最重要的蛋白质极大地增强了该项目的重要性”