Programmed translation arrest controlled by nascent peptides and antibiotics

由新生肽和抗生素控制的程序化翻译停滞

• 批准号: 8422205
• 负责人: ALEXANDER S MANKIN
• 金额: $ 30.31万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8422205
• 关键词: Affect; Amino Acids; Amino Acyl Transfer RNA; Antibiotic Resistance; Antibiotics; Bacterial Infections; Binding Sites; Cells; Cistrons; Genes; Investigation; Knowledge; Macrolide Antibiotics; Macrolide-resistance; Macrolides; Modern Medicine; Molecular; Molecular Weight; Peptide Antibiotics; Peptides; Pharmaceutical Preparations; Physiological; Property; Regulation; Resistance; Ribosomes; Role; Signal Transduction; Structure; System; Translations; clinically relevant; cofactor; combat; leucylarginine; novel strategies; pathogen; programs; response; sensor; small molecule; tool

DESCRIPTION (provided by applicant): ABSTRACT The ribosome can functionally respond to specific nascent peptides. Such response, which can be additionally affected by small molecular weight cofactors, is a key component of the mechanism of control of important bacterial and eukaryotic genes. However, the molecular mechanisms of recognition of the regulatory nascent peptide and cofactor and the basic principles of the ribosomal response are poorly understood. Expression of a number of inducible antibiotic resistance genes in bacterial pathogens is controlled by nascent peptide-dependent programmed translation arrest promoted by antibiotic. Recently, a distinct class of regulatory nascent peptides encoded in the regulatory cistrons of many macrolide resistance genes has been identified. The peptides of this class are characterize dby the presence of an 'RLR' (Arg-Leu-Arg) motif. Preliminary studies showed that the mechanism of programmed translation arrest directed by these peptides is principally different from all of the previously studied systems. Furthermore, nascent peptides as short as three or four amino acids were found to be sufficient to direct drug-dependent ribosome arrest thereby yielding the shortest known stalling peptides. Such minimalistic stalling nascent peptides and the knowledge of the exact binding site of the stalling cofactor (the inducing antibiotic) provide unprecedented tools for unraveling important fundamental aspects of the general mechanisms of nascent peptide- and small cofactor-controlled programmed translation arrest. In the three specific aims of this proposal we will 1) explore the structural features of the minimalist nascent peptide required for directing ribosome stalling, 2) analyze the role of the antibiotic cofactor in programmed translation arrest, and 3) unravel the mechanism of the stalling signal recognition and structural features of the ribosome in the arrested state. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE One of the major challenges of modern medicine is combating the spread of resistance to antibiotics. Many bacterial pathogens activate expression of the resistance genes in response to the presence of antibiotics. Understanding the molecular mechanisms of inducible resistance will, among other applications, pave the way for novel strategies to develop superior drugs capable of curbing bacterial infections.

描述(由申请人提供)： 摘要核糖体可以对特定的新生多肽产生功能性反应。这种反应还可以受到小分子辅助因子的影响，是重要细菌和真核基因控制机制的关键组成部分。然而，对调节新生多肽和辅因子的分子识别机制以及核糖体反应的基本原理还知之甚少。一些可诱导的抗生素耐药基因在细菌病原菌中的表达受抗生素促进的新生多肽依赖的程序性翻译停滞控制。最近，在许多大环内酯类耐药基因的调控顺反子中发现了一类独特的调节性新生多肽。这类多肽的特征是存在一个‘RLR’(Arg-Leu-Arg)基序。初步研究表明，这些多肽引导的程序性翻译抑制机制与以往研究的所有系统基本不同。此外，研究发现，短至三到四个氨基酸的新生多肽足以指导药物依赖的核糖体停滞，从而产生已知最短的停滞肽。这种极简主义的停滞新生多肽和对停滞辅助因子(诱导抗生素)的确切结合位置的了解，为解开新生多肽和小辅助因子控制的程序性翻译停滞的一般机制的重要基础方面提供了前所未有的工具。在这项建议的三个具体目标中，我们将1)探索指导核糖体停滞所需的最低限度新生多肽的结构特征，2)分析抗生素辅因子在程序性翻译停滞中的作用，3)揭示停滞信号识别的机制和停滞状态下核糖体的结构特征。 公共卫生相关性： 项目描述现代医学的主要挑战之一是抗击抗生素耐药性的传播。许多细菌病原体在抗生素存在的情况下激活耐药基因的表达。了解可诱导耐药性的分子机制，以及其他应用，将为开发能够遏制细菌感染的优势药物的新策略铺平道路。