Multivalent Ligands as Effectors

描述(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，信号是通过化学受体及其相关信号蛋白的大分子组装来传递的。一个最重要的研究目标是了解这种高阶蛋白质组装传递信号的能力所依据的分子机制。这个应用程序的三个具体目标如下。目标1是将合成配体、蛋白质工程和纳米颗粒与电子冷冻断层扫描相结合，以确定信号阵列的组织以及化学效应剂如何影响它。目标2是实施与天然膜制剂兼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。目标3是利用目标1和目标2中开发的工具来探索微生物趋化反应和成群之间的关系。在追求这些目标时，我们将运用有机化学、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，这项研究将为深入了解细菌中趋化信号和群集的分子机制，以及探索一般信号转导途径的新工具和策略提供帮助。

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.