Project 1: Structure, function, and inhibition of SEDS-family peptidoglycan polymerases

项目摘要 项目1：SEDS家族肽聚糖聚合酶的结构、功能和抑制 肽聚糖细胞壁对于几乎所有细菌的生存力和生长都是必不可少的，并且干扰肽聚糖细胞壁的药物也是如此。 细胞壁组装是最有效的抗生素之一。构建肽聚糖细胞壁需要聚糖 通过糖基转移酶催化的链延伸和通过青霉素催化的肽交联， 结合蛋白（PBPs）。在项目1中，我们将研究一个新发现的完整膜家族， 称为形状、延伸、分裂和孢子形成（“SEDS”）的肽聚糖糖基转移酶 proteins. SEDS家族中的蛋白质存在于所有具有肽聚糖细胞壁的细菌中，并且它们是必需的 这使它们成为理想的抗生素靶标。在这个项目中，我们将研究SEDS蛋白的功能，使用 结构生物学和化学生物学方法的结合。具体来说，我们将研究1）SEDS如何 蛋白质被PBPs变构激活并催化肽聚糖合成，2）原型SEDS如何 蛋白质在称为杆复合体的大型多蛋白质细胞延伸机器的背景下的功能，以及3） SEDS蛋白在分裂细胞分裂机制中是如何组织和调节的。总的来说，这个项目 将导致对SEDS蛋白功能的详细机制理解的发展，以及 发现了这一重要蛋白质类的新化学抑制剂。

PROJECT SUMMARY Project 1: Structure, function, and inhibition of SEDS-family peptidoglycan polymerases The peptidoglycan cell wall is essential for viability and growth in nearly all bacteria, and drugs that interfere with cell wall assembly are among the most effective antibiotics. Building a peptidoglycan cell wall requires glycan strand elongation catalyzed by glycosyltransferase enzymes and peptide crosslinking catalyzed by penicillin- binding proteins (PBPs). In Project 1, we will investigate a newly discovered family of integral membrane peptidoglycan glycosyltransferase enzymes called shape, elongation, division and sporulation (“SEDS”) proteins. Proteins in the SEDS family are found in all bacteria with a peptidoglycan cell wall and they are essential for growth, making them ideal antibiotic targets. In this project, we will investigate SEDS protein function using a combination of structural biology and chemical biology approaches. Specifically, we will investigate 1) how SEDS proteins are allosterically activated by PBPs and catalyze peptidoglycan synthesis, 2) how a prototypical SEDS protein functions in the context of a large multi-protein cell elongation machine called the Rod complex, and 3) how SEDS proteins are organized and regulated in the divisome cell division machinery. Collectively, this project will lead to the development of a detailed mechanistic understanding of SEDS protein function as well as the discovery of new chemical inhibitors of this important protein class.