Modeling Ribosomal Control, Function and Assembly

核糖体控制、功能和组装建模

基本信息

批准号：
7681539
负责人：
ROBERT L JERNIGAN
金额：
$ 25.03万
依托单位：
IOWA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-25 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7681539
关键词：
Active Sites Address Adopted Affect Amino Acyl Transfer RNA Antibiotics Antineoplastic Agents Binding Binding Sites Biochemical Biological Process Cellular biology Cereals Chemicals Collaborations Collection Communities Complex Comprehension Computer Assisted Computing Methodologies Data Databases Deposition Drug Design Equilibrium Foundations Goals Hereditary Disease Imagery Individual Internet Laboratories Learning Literature Messenger RNA Methodology Methods Modeling Modification Molecular Molecular Conformation Molecular Models Molecular Structure Molecular Target Motion Outcome Pathway interactions Pattern Peptides Peptidyltransferase Pharmaceutical Preparations Positioning Attribute Printing Process Protein Biosynthesis Protein Dynamics Protein Subunits Proteins RNA RNA Folding Reporting Research Research Personnel Resort Ribosomes Role Simulate Site Solutions Staging Structure System Time Transfer RNA Validation Work base cellular imaging computerized tools driving force experience flexibility foot innovation insight interest meetings molecular modeling network models novel therapeutic intervention programs protein folding research study scaffold simulation single-molecule FRET small molecule success theories tool

项目摘要

DESCRIPTION (provided by applicant): The ribosome is a well-known target for antibiotics, genetic diseases, and anti-cancer drugs, but its actual mechanism of action is not yet understood in detail. The availability of a number of structures of the ribosome in different states now presents an important opportunity to achieve the overall goals to unravel the steps involved in the translocation of the tRNAs and mRNA, protein elongation, and the assembly of the 30S subunit protein components onto the 16S RNA scaffold. The project is built upon previous successes in 1) experimental foot printing experiments for identifying intermediates in the assembly process and 2) computing the important large domain motions of proteins and RNAs by coarse-graining the structures, represented as an elastic network, revealing the structural motions through normal mode analysis. Thus it becomes feasible to compute the motions of the entire ribosome structure, yielding information about how the various components engage together or in opposition, as well as visualizing the motions. By adopting a mixed coarse-grained approach, the large domain motions and at the same time the intricate atomic details at binding sites, active sites, and hinges are revealed within the structure. Validation of the predicted changes in conformation and suggested mechanisms of function will come from experimental data such as FRET and single molecule experiments. For the 30S ribosomal subunit assembly, molecular models will be developed for assembly intermediates by utilizing these robust computations to generate structures consistent with new modification experiments indicating conformational changes. This innovative coordination of experiments and computations will enhance the utility of both groups of studies. Extensive simulations of the structural dynamics of the ribosome, combined with the various known structural, biochemical, and sequence conservation data are expected to yield important new molecular details of how this ribonucleo-protein machine functions, opening prospects for new therapeutic approaches.

描述（申请人提供）：核糖体是众所周知的抗生素、遗传病和抗癌药物的靶标，但其实际作用机制尚不清楚。不同状态下核糖体的多种结构的可用性现在为实现总体目标提供了一个重要的机会，以阐明 tRNA 和 mRNA 易位、蛋白质延伸以及 30S 亚基蛋白质组分组装到蛋白质上所涉及的步骤。 16S RNA 支架。该项目建立在之前的成功基础上：1）用于识别组装过程中中间体的实验足迹实验，以及 2）通过粗粒度结构（表示为弹性网络）计算蛋白质和 RNA 的重要大域运动，揭示了结构通过简正模态分析进行运动。因此，计算整个核糖体结构的运动变得可行，产生有关各个组件如何结合在一起或相反的信息，以及可视化运动。通过采用混合粗粒度方法，大域运动以及同时结合位点、活性位点和铰链处的复杂原子细节在结构内得以揭示。预测的构象变化和建议的功能机制的验证将来自 FRET 和单分子实验等实验数据。对于 30S 核糖体亚基组装，将利用这些稳健的计算来开发组装中间体的分子模型，以生成与表明构象变化的新修饰实验一致的结构。这种实验和计算的创新协调将增强两组研究的实用性。对核糖体结构动力学的广泛模拟，结合各种已知的结构、生化和序列保守数据，预计将产生关于这种核糖核蛋白机器如何运作的重要的新分子细节，为新的治疗方法开辟前景。