STRUCT BAS FOR PEPTIDOGLYCAN RECOGNITION BY HUMAN PEPTIDOGLYCAN RECOGNITION

人类肽聚糖识别的肽聚糖识别的结构基础

• 批准号: 7955594
• 负责人: Roy A Mariuzza
• 金额: $ 1.17万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7955594
• 关键词: Affinity; Amidohydrolases; Bacteria; Bacterial Infections; Binding; Cell Wall; Complex; Computer Retrieval of Information on Scientific Projects Database; Data Collection; Funding; Grant; Host Defense; Housing; Human; Hydrolysis; Immune system; Inflammatory Response; Insecta; Institution; Mammals; N-Acetylmuramoyl-L-alanine Amidase; N-terminal; Pattern Recognition; Peptides; Peptidoglycan; Play; Protein Binding; Proteins; Publishing; Research; Research Personnel; Resolution; Resources; Role; Sequence Homology; Signal Pathway; Source; Structure; TLR4 gene; United States National Institutes of Health; Work; amidase; antimicrobial; antimicrobial peptide; bactericide; cell dimension; detector; insight; pathogen; peptidoglycan recognition protein

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Peptidoglycan recognition proteins (PGRPs) are pattern recognition molecules of the innate immune system that bind and, in certain cases, hydrolyze peptidoglycans (PGNs) of bacterial cell walls (1). They are highly conserved from insects to mammals. PGRPs bind PGNs with high affinity and are important contributors to host defense against bacterial infections. Insects PGRPs, of which there are at least 19, are involved in activating signaling pathways that induce expression of anti-microbial peptides. By contrast, mammalian PGRPs, of which there are four, do not act through host signaling pathways, but are directly bactericidal against both Gram-positive and -negative bacteria (1). Indeed, these PGRPs are a new class of bactericidal proteins that have a different structure and mechanism of action than currently known mammalian antimicrobial peptides. Mammalian PGRP-L is an N-acetylmuramoyl-L-alanine amidase that hydrolyzes PGN. Very recently, it was found that PGRP-L also has a proinflammatory function, unrelated to its amidase activity (2). We previously published structures of human PGRP-Ialpha and -Ibeta in complex with PGN fragments, and have proposed a mechanism for their bactericidal activity (3,4). We now plan to extend our work to PGRP-L, which contains a large N-terminal domain with no sequence homology to other known proteins, and whose structure remains to be established. The PGRP-L structure will provide insights into how three different types of pattern recognition molecules (PGRPs, Nod2 and TLR4) play interdependent roles in inflammatory responses to bacterial pathogens. Recently, We obtained a few small crystals which are too small (~50um) for data collection with our in-house detector. They diffract to a maximum resolution of 7 ¿ with unit cell dimensions of

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 肽聚糖识别蛋白（PGRP）是固有免疫系统的模式识别分子，该系统结合并在某些情况下水解了细菌细胞壁的肽聚糖（PGN）（1）。它们是从昆虫到哺乳动物的高度保守的。 PGRP结合具有高亲和力的PGN，是宿主防御细菌感染的重要贡献者。昆虫PGRP，其中至少有19个，参与了影响抗微生物胡椒体表达的信号通路。相比之下，有四种的哺乳动物PGRP不通过宿主信号通路起作用，而是直接针对革兰氏阳性和阴性细菌的细菌（1）。实际上，这些PGRP是一类新的细菌蛋白，其作用结构和作用机理与当前已知的哺乳动物抗菌胡椒粉不同。哺乳动物PGRP-L是一种水解PGN的N-乙酰毛毛酰酰酰酰酰酰酰氨酸酰胺酶。最近，发现PGRP-L还具有促炎功能，与其胺化酶活性无关（2）。我们以前在与PGN片段中发表了人类pgrp -ialpha和-ibeta的结构，并提出了一种用于其细菌活性的机制（3,4）。现在，我们计划将我们的工作扩展到PGRP-L，其中包含一个大型的N末端结构域，与其他已知蛋白质没有序列同源性，并且其结构仍有待确定。 PGRP-L结构将提供有关三种不同类型的模式识别分子（PGRP，NOD2和TLR4）如何在对细菌病原体的炎症反应中起着相互依存的作用的见解。最近，我们获得了一些小晶体，这些晶体太小（〜50um），无法使用我们的内部检测器收集数据。它们衍射到最大分辨率为7€，具有单位电池尺寸