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

项目1：SEDS家族肽聚糖聚合酶的结构、功能和抑制

基本信息

批准号：
10699954
负责人：
Andrew Kruse
金额：
$ 77.55万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-07 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10699954
关键词：
Achievement Antibiotic Resistance Antibiotics Bacteria Bacterial Infections Binding Proteins Biogenesis Biology Catalytic Domain Cell Survival Cell Wall Cell division Cell physiology Cells Cellular Morphology Chemicals Complex Cryoelectron Microscopy Cytokinesis Development Dissection ESKAPE pathogens Enzymes Family Goals Growth Heart Individual Infection Investigation Macromolecular Complexes Maintenance Mediating Membrane Membrane Proteins Molecular Molecular Conformation Penicillin-Binding Proteins Peptides Peptidoglycan Peptidoglycan glycosyltransferase Peptidyltransferase Pharmaceutical Preparations Polymerase Polymers Polysaccharides Production Protein Biochemistry Protein Family Proteins Publishing Regulation Reporting Resistance Rod Role Sampling Shapes Structure Thermus thermophilus Time United States Vertebral column Work X-Ray Crystallography bacterial genetics cell envelope combat crosslink drug discovery glycosyltransferase inhibitor insight member muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol new therapeutic target novel novel therapeutics polymerization protein complex protein function protein structure structural biology success targeted treatment therapeutic development therapeutically effective tool

项目摘要

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.

项目概要项目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和生长至关重要，并且药物会干扰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糖基转移酶催化的链延伸和青霉素催化的肽交联结合蛋白（PBP）。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（“SEDS”）的肽聚糖糖基转移酶蛋白质。 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，并且它们是必需的生长，使它们成为理想的抗生素靶点。在这个项目中，我们将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 PBP 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中发挥作用，以及 3) SEDS 蛋白如何在分裂细胞分裂机制中组织和调节。总的来说，这个项目将导致对 SEDS 蛋白功能的详细机制理解以及发现这一重要蛋白质类别的新化学抑制剂。