Multivalent Ligands as Effectors

描述（由申请人提供）：拟议研究的长期目标是以化学术语描述导致细菌趋化性的信号转导途径。细菌趋化性信号系统已经成为跨膜信号和分子信息处理的原型。对该系统的研究表明，信号通过化学感受器及其相关信号蛋白的大分子组装体传递。最前沿的研究目标是了解这种高阶蛋白质组装体传递信号能力的分子机制。本申请的三个具体目标如下。目的1是使用合成配体，蛋白质工程，纳米粒子结合电子cryotomography，以确定组织的信号阵列和如何chemoeffectors影响it. Aim 2是实施化学生物学策略与天然膜制剂兼容，以阐明蛋白质-蛋白质相互作用的表面重建的信号晶格。目的3是使用目的1和2中开发的工具来探索趋化性和群集的微生物响应之间的关系。在追求这些目标时，我们将采用有机化学，微生物学，蛋白质工程，聚合物和材料化学，结构生物学和化学生物学的方法和思想。我们预计，这项研究将提供深入了解细菌中趋化性信号和群集的分子机制，以及探索信号转导途径的新工具和策略。 公共卫生相关性：细胞检测和响应分子信号的能力对其生存至关重要。在识别和表征细胞中传递信号的细胞组分的功能方面已经取得了巨大的进步，但即使是一种途径也缺乏化学水平的理解。这项拟议中的研究将汇集一系列不同的方法，以确定蛋白质复合物如何发挥作用，使细菌“运行”到引诱剂或远离驱避剂。

DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to describe the signal transduction pathway that leads to bacterial chemotaxis in chemical terms. The bacterial chemotaxis signaling system has emerged as an archetype for transmembrane signaling and molecular information processing. Investigations of this system have revealed that signals are transmitted through a macromolecular assembly of the chemoreceptors and their associated signaling proteins. A forefront research objective is to understand the molecular mechanisms that underlie the ability of this higher order protein assembly to transmit signals. The three Specific Aims of this application follow. Aim 1 is to use synthetic ligands, protein engineering, and nanoparticles in conjunction with electron cryotomography to determine the organization of the signaling array and how chemoeffectors influence it. Aim 2 is to implement chemical biology strategies compatible with native membrane preparations to elucidate protein-protein interaction surfaces in the reconstituted signaling lattice. Aim 3 is to probe the relationship between the microbial responses of chemotaxis and swarming using tools developed in Aims 1 and 2. In pursuing these Aims, we shall employ methods and ideas from organic chemistry, microbiology, protein engineering, polymer and materials chemistry, structural biology, and chemical biology. We anticipate that this research will provide insight into the molecular mechanisms that underlie chemotactic signaling and swarming in bacteria as well as new tools and strategies to explore signal transduction pathways in general. PUBLIC HEALTH RELEVANCE: The ability of cells to detect and respond to molecular signals is essential for their survival. Tremendous strides have been made in identifying and characterizing the function of cellular components that transmit signals in cells, but a chemical level understanding of even one pathway is lacking. The proposed research will bring together a diverse set of approaches to determine how complexes of proteins function to cause bacteria to "run" toward attractants or away from repellents.