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：
9900030
负责人：
DOROTHY BECKETT
金额：
$ 32.12万
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 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900030
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/antagonist 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.

项目概要/摘要尽管它对生物学的重要性早已被认识到二十世纪以来，变构的分子机制仍然是深入研究的课题。在变构中，来自蛋白质中一个位点的信号被传递到通常较远的第二个位点，网站改变其功能。集成模型提供了一个框架，其中动态和/或结构变化即使在单个蛋白质。挑战在于破译哪些分子过程对于信号至关重要传播。在这项工作中，我们将研究第二组的变构机制生物素蛋白连接酶，大肠杆菌 BirA 蛋白。我们假设发生了 BirA 变构通过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进化变构，同时保留翻译后生物素的基本酶促功能添加。这些假设将使用综合遗传筛查、解决方案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 BirA 变构如何运作将提高我们对变构机制，可能有助于开发选择性靶向药物特定的微生物 BPL 以及创建基于生物素蛋白连接酶的技术工具。