Structure and Modeling

结构和建模

基本信息

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
项目类别：
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

项目摘要

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骨干结构和配体结合位点膜蛋白药物使用与最佳可用的方法相兼容的方法这些蛋白质的膜模拟环境。通过使用解决方案和固态NMR 光谱法我们旨在跨验证双层和胶束的结构表征，并采用两种方法优势的优势。建模和计算工作将用于完善分子结构通过利用所有结构约束和我们的集体膜蛋白生物物理知识以彻底表征这些潜在的药物靶标。此信息将提供进一步了解其在项目1和2中的生物学功能。结构也将有助于项目2中对靶蛋白具有高亲和力的化合物的鉴定。该项目中的研究由三个目的描述：1）解决方案和固态样本准备工作 NMR; 2）主干结构和部分侧链结构和动力学的结构表征； 3）初始模型的结构改进，用于绘制结构和功能含义。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学院和UCSD，并与其他每个项目和科学核心完全融合在一起该程序。确实，如果没有其他计划项目的努力，就无法执行该项目。靶向最重要的蛋白质会大大提高该项目的重要性”