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

项目总结 项目1：SEDS家族肽聚糖聚合酶的结构、功能和抑制作用 肽聚糖细胞壁对几乎所有细菌的生存和生长都是必不可少的，而干扰 细胞壁组装是最有效的抗生素之一。构建肽多聚糖细胞壁需要多糖 糖基转移酶催化的链延长和青霉素催化的多肽交联- 结合蛋白(PBPs)。在项目1中，我们将研究一个新发现的整体膜家族 称为形状、伸长、分裂和孢子形成的肽聚糖糖基转移酶(“SED”) 蛋白质。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，它们是必不可少的 以促进生长，使它们成为理想的抗生素靶标。在这个项目中，我们将使用一种 结构生物学和化学生物学相结合的方法。具体地说，我们将调查1)SED如何 蛋白质被PBPs变构激活并催化肽聚糖的合成，2)典型的SEDS 蛋白质在称为杆状复合体的大型多蛋白质细胞伸长机的背景下发挥功能，以及3) SEDS蛋白在分裂体细胞分裂机制中是如何组织和调节的。总体而言，这个项目 将导致对SEDS蛋白质功能的详细机制理解以及 发现这一重要蛋白质类的新的化学抑制剂。

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.