Biochemistry of Class I lysyl-tRNA synthetases

I 类赖氨酰-tRNA 合成酶的生物化学

• 批准号: 6573198
• 负责人: MICHAEL IBBA
• 金额: $ 25.96万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6573198
• 关键词: active sites; aminoacid analog; aminoacid tRNA ligase; bacterial proteins; biochemical evolution; enzyme mechanism; lysine; protein engineering

DESCRIPTION (provided by applicant): Aminoacyl-tRNA synthetases are essential for the correct pairing of amino acids and tRNAs during protein synthesis. Most aminoacyl-tRNA synthetases belong to one of two unrelated structural classes. The only widespread exceptions are the lysyl-tRNA synthetases, which are class I enzymes in certain bacteria and archaea but are otherwise members of class I1. The class I lysyl-tRNA synthetase is found in a number of pathogenic bacteria and is fundamentally different from the human class II enzyme, identifying the class I bacterial enzyme as a potential target for developing anti-infective agents. The aim of this proposal is to investigate structure/function relationships in the recently discovered class I-type lysyl-tRNA synthetases. The major goals include: i) Determining how class I and class II lysyl-tRNA synthetases recognize and discriminate between lysine and lysine analogues. ii) Identifying the protein-RNA interactions that determine lysine tRNA recognition in vitro and in vivo. The results of these experiments will reveal how the same activity (attachment of lysine to lysine tRNA) can be achieved within two completely different structural frameworks. This, in turn, will provide a framework for developing therapeutics specifically targeted against the class I lysyl-tRNA synthetase.

描述（由申请人提供）：氨酰基-tRNA 合成酶对于蛋白质合成过程中氨基酸和 tRNA 的正确配对至关重要。大多数氨酰基-tRNA 合成酶属于两个不相关的结构类别之一。唯一普遍存在的例外是赖氨酰-tRNA 合成酶，它在某些细菌和古细菌中属于 I 类酶，但在其他情况下属于 I1 类酶。 I 类赖氨酰-tRNA 合成酶存在于许多病原菌中，与人类 II 类酶根本不同，因此将 I 类细菌酶确定为开发抗感染药物的潜在靶点。本提案的目的是研究最近发现的 I 类赖氨酰-tRNA 合成酶的结构/功能关系。主要目标包括： i) 确定 I 类和 II 类赖氨酰-tRNA 合成酶如何识别和区分赖氨酸和赖氨酸类似物。 ii) 鉴定决定赖氨酸 tRNA 体外和体内识别的蛋白质-RNA 相互作用。这些实验的结果将揭示如何在两个完全不同的结构框架内实现相同的活性（赖氨酸与赖氨酸 tRNA 的连接）。反过来，这将为开发专门针对 I 类赖氨酰-tRNA 合成酶的疗法提供框架。