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Structural Interactions of Bacterial Adhesin with Glycosaminoglycans

细菌粘附素与糖胺聚糖的结构相互作用

基本信息

批准号：
8400895
负责人：
Xu Wang
金额：
$ 22.66万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
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：
2009-09-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8400895
关键词：
Address Adhesions Affinity Age Anti-Adhesion Agent Antibiotic Resistance Area Bacteria Bacterial Adhesins Bacterial Adhesion Binding Binding Proteins Binding Sites Biochemical Biological Borrelia burgdorferi Carbohydrates Cell physiology Cell surface Cells Chemicals Chondroitin Sulfates Complex Core Protein Country Cytoplasmic Structures Cytoplasmic Tail Dermatan Sulfate Development Docking Drug Formulations Event Foundations Glycobiology Glycopeptides Glycoproteins Glycosaminoglycans Goals Health Homology Modeling Human Immune system Infection Inorganic Sulfates Instruction Interdisciplinary Study Knowledge Learning Lipids Lipoproteins Lyme Disease Mammalian Cell Membrane Mentors Methodology Methods Microbe Modeling Modification Mutation Nature Phase Polysaccharides Process Protein Binding Protein Isoforms Proteins Proteoglycan Public Health Relaxation Research Research Institute Resolution Role Signal Transduction Skin Solutions Spin Labels Structure Supervision Surface System Techniques Tissues Training Universities Unspecified or Sulfate Ion Sulfates Vector-transmitted infectious disease Work antimicrobial antimicrobial drug base career cell motility combat decorin decorin binding protein B dermatan sulfate chondroitin sulfate design falls pathogenic bacteria prevent protein complex protein protein interaction protein structure restraint

项目摘要

Antibiotic resistance is becoming an imminent health threat. One strategy for combating this is to inhibit the adhesion of microbes to human cells. However, specific structural interactions between microbes and target cells are not well characterized, thus hampering the development of new anti-microbial agents. This proposal strives to overcome this deficiency by conducting an in-depth structural study of the interactions between bacterial adhesins and glycosaminoglycans (GAGs), a ubiquitous polysaccharide found on the surface of cells and a primary target for bacterial adhesins. The focus of the proposal will be on the decorin binding protein (dbp), an adhesin from Borrelia burgdorferi, the etiological agent of Lyme disease. To study the interactions between GAGs and dbp, the structures of dbp in both cytoplasmic and its native lipoprotein form will be solved using solution NMR. Using these structures as bases, dbp's interactions with heterogeneous and homogeneous GAG oligomers will be determined. The main goal of this research is to obtain high resolution structures of dbp complexed to GAG and deduce from these structures the specific interactions between GAG and dbp that can be targeted to prevent the adhesion of bacteria to human cells. Finally, as GAGs often exist in the form of proteoglycans, an attempt will be made to characterize the interactions between dbp and intact decorin, the proteoglycan that dbp primarily targets. The main goal for this portion of the proposal will be to construct the complex structure of dbp with intact decorin utilizing only NMR derived orientational restraints and the dimeric nature of intact decorin. The proposed work will be carried out at the Complex Carbohydrate Research Center, a multidisciplinary research institute and one of the country's premier glycobiology research centers. The candidate's long term career goal is to understand the rules governing the interactions of GAGs with its protein targets and devise strategies for steering these interactions in a desired direction. The candidate's immediate goal during the mentored phase will be to acquire proficiency with the chemical and biochemical methods used to purify GAG oligomers and learn the use of mammalian expression systems that will be crucial for obtaining intact decorin. The knowledge of these techniques will enable the candidate to conduct independent research in the proposed area.

抗生素耐药性正在成为迫在眉睫的健康威胁。对付这种情况的一个策略是抑制微生物对人体细胞的粘附。然而，微生物和靶标之间的特定结构相互作用细胞的特性还不清楚，因此阻碍了新的抗微生物剂的开发。这一项提案试图通过对相互作用进行深入的结构研究来克服这一缺陷细菌粘附素和糖胺聚糖（GAG）之间的关系，细胞表面和细菌粘附素的主要靶标。提案的重点将放在装饰上。结合蛋白（DBP），一种来自莱姆病病原体伯氏疏螺旋体的粘附素。研究 GAGs与DBP之间的相互作用，DBP在胞浆和天然脂蛋白中的结构将使用溶液NMR解析形式。以这些结构为基础，DBP与将测定非均相和均相GAG寡聚体。这项研究的主要目的是获得与GAG复合的DBP的高分辨率结构，并从这些结构中推导出特异性 GAG和DBP之间的相互作用，其可以被靶向以防止细菌粘附到人细胞。最后，由于GAG通常以蛋白聚糖的形式存在，因此将尝试表征GAG的特性。 DBP和完整的核心蛋白聚糖（DBP主要靶向的蛋白聚糖）之间的相互作用。的主要目标这部分的建议将是构建具有完整核心蛋白聚糖的DBP的复杂结构，完整核心蛋白聚糖的NMR衍生取向限制和二聚体性质。拟议的工作将在复杂碳水化合物研究中心进行，这是一个多学科的研究中心。研究所和该国首屈一指的糖生物学研究中心之一。候选人的长期我的职业目标是了解GAG与其蛋白质靶点相互作用的规律，将这些互动引向所需方向的策略。候选人在选举期间的直接目标指导阶段将是获得与用于纯化的化学和生物化学方法的熟练程度 GAG寡聚体，并学习使用哺乳动物表达系统，这将是至关重要的获得完整的核心蛋白聚糖。这些技术的知识将使候选人能够进行独立的研究，建议的地区。