Sortase A anchoring mechanism

分选酶A锚定机制

• 批准号: 6829819
• 负责人: DEBORAH LEON-ROSSELL
• 金额: $ 2.92万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2008-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6829819
• 关键词: Staphylococcus aureus; aminoacid; aminoacyltransferase; bacteria infection mechanism; cell adhesion; drug design /synthesis /production; enzyme activity; enzyme complex; enzyme inhibitors; enzyme mechanism; enzyme structure; enzyme substrate; host organism interaction; nuclear magnetic resonance spectroscopy; predoctoral investigator; protein binding; protein structure function

DESCRIPTION (provided by applicant): Gram-positive bacteria adhere to specific tissues in animals using the surface proteins displayed on their cell wall. These surface proteins promote bacterial adhesion, evasion of the host immune system and invasion of the host organism. The enzymes responsible for attaching these proteins to the cell wall are called sortases and they are found in all gram-positive bacteria. The focus of this proposal is to study sortase A (SrtA) from Staphylococcus aureus. To obtain a better understanding of the universal anchoring mechanism of sortases we will design and test the enzymatic effectiveness of several inhibitors of SrtA. We also propose to elucidate the structure of the SrtA-inhibitor complex by using NMR spectroscopy. We will identify the amino acids that are important for catalysis and substrate binding by introducing single amino acid mutations in SrtA. The knowledge gained from this study will hopefully lead to ways of disabling this anchoring mechanism and thereby preventing bacterial infection. Work leading to the creation of anti-infective agents against pathogenic bacteria should be prioritized especially in an era where bacteria have developed a resistance to many commonly used antibiotics.

描述（由申请人提供）：革兰氏阳性细菌使用其细胞壁上显示的表面蛋白粘附在动物中的特定组织。这些表面蛋白会促进细菌粘附，逃避宿主免疫系统和侵入宿主生物体。负责将这些蛋白质附着在细胞壁上的酶称为排序酶，并且在所有革兰氏阳性细菌中都发现它们。该提案的重点是研究金黄色葡萄球菌的排序酶A（SRTA）。为了更好地了解排序酶的通用锚定机制，我们将设计和测试SRTA抑制剂的酶促有效性。我们还建议使用NMR光谱法阐明SRTA抑制剂复合物的结构。我们将通过在SRTA中引入单个氨基酸突变来确定对催化和底物结合至关重要的氨基酸。从这项研究中获得的知识将有望导致禁用这种锚定机制并防止细菌感染的方法。应优先考虑导致抗感染剂对致病细菌产生抗感染剂的工作，尤其是在细菌对许多常用抗生素产生抗性的时代。