Multivalent Ligands as Effectors

描述（由申请人提供）：拟议研究的长期目标是用化学术语描述导致细菌趋化的信号转导途径。细菌趋化信号系统已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，信号是通过化学感受器及其相关信号蛋白的大分子组装传递的。一个前沿的研究目标是了解这种高阶蛋白质组装传输信号能力的分子机制。以下是该应用程序的三个特定目标。目的1是使用合成配体、蛋白质工程和纳米颗粒结合电子冷冻层析成像来确定信号阵列的组织以及化学效应物如何影响它。目的2是实施与天然膜制备相容的化学生物学策略，以阐明重组信号晶格中的蛋白质-蛋白质相互作用表面。目的3是利用目的1和2中开发的工具探索趋化性微生物反应与蜂群之间的关系。为了实现这些目标，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趋化信号和群体的分子机制，以及探索一般信号转导途径的新工具和策略。

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.