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Signal Propagation in Protein Allostery: Mechanism and Evolution

蛋白质变构中的信号传播：机制和进化

基本信息

批准号：
10326378
负责人：
David Joseph Weber
金额：
$ 32.35万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10326378
关键词：
Allosteric Regulation Amino Acid Substitution Bacteria Bacterial Infections Binding Biochemical Biological Process Biology Biotin Coupled Coupling Disease Distant Drug Targeting E coli birA protein Engineering Enzymes Escherichia coli Evolution Gene Expression Genetic Screening Ligase Malignant Neoplasms Metabolism Modeling Molecular Movement Mycobacterium tuberculosis Organism Pathogenicity Pathway Analysis Pharmaceutical Preparations Population Post-Translational Protein Processing Process Proteins Research Role Series Signal Transduction Site Staphylococcus aureus Structure System Technology Testing Thermodynamics Work X-Ray Crystallography base biophysical analysis biophysical properties computer studies computerized tools drug development falls gene repression genetic corepressor improved inhibitor innovation insight microbial molecular dynamics nervous system disorder novel strategies pathogenic bacteria preservation protein function small molecule tool transmission process

项目摘要

Project Summary/Abstract Although its significance for biology has been recognized for more than a century, the molecular mechanism of allostery remains the subject of intense research. In allostery a signal from one site in a protein is transmitted to a second, often distant, site to alter its function. The ensemble model provides a framework in which dynamic and/or structural changes can contribute to allosteric regulation even within a single protein. The challenge lies in deciphering which molecular processes are critical to signal transmission. In this work we will investigate the allosteric mechanism in the Group II Biotin Protein Ligase, E.coli BirA protein. We hypothesize that BirA allostery occurs through direct coupling of dynamic changes in multiple loops to formation of residue networks. We further hypothesize that this mechanism allowed for the evolution of allostery while preserving an essential enzymatic function in post-translational biotin addition. These hypotheses will be tested using integrated genetic screening, solution biophysical measurements, x-ray crystallography, and molecular dynamics simulations. The elucidation of how allostery works in BirA will improve our general understanding of allosteric mechanisms and may prove useful for developing drugs that selectively target specific microbial BPLs and for creating Biotin Protein Ligase-based technology tools.

项目总结/摘要尽管它对生物学的重要性已经被认识了超过一个世纪，世纪以来，变构的分子机制一直是研究的热点。在变构中，来自蛋白质一个位点的信号被传递到第二个位点，通常是遥远的，改变其功能。集成模型提供了一个框架，其中动态和/或结构变化可有助于变构调节，蛋白挑战在于破译哪些分子过程对信号至关重要传输在这项工作中，我们将调查的变构机制，在第二组生物素蛋白连接酶，大肠杆菌BirA蛋白。我们假设BirA变构发生在通过将多个循环中的动态变化直接耦合到残留物的形成，网络.我们进一步假设，这种机制允许变构同时保留翻译后生物素中的基本酶功能的增订条文这些假设将使用综合遗传筛查、解决方案和方法进行测试。生物物理测量、X射线晶体学和分子动力学模拟。阐明变构在BirA中的作用方式将有助于我们对变构机制，并可能证明用于开发药物，选择性靶向特定微生物BPL和用于创建基于生物素蛋白质连接酶的技术工具。