Biochemistry of Class I lysyl-tRNA synthetases

描述(由申请人提供)：氨基酰-tRNA合成酶对于蛋白质合成过程中氨基酸和tRNA的正确配对是必不可少的。大多数氨酰-tRNA合成酶属于两个不相关的结构类别之一。唯一普遍的例外是赖氨酰-tRNA合成酶，它在某些细菌和古菌中是I类酶，但在其他情况下是I1类的成员。I类赖氨酰-tRNA合成酶存在于许多病原菌中，与人类II类酶有根本的不同，使I类细菌酶成为开发抗感染药物的潜在靶点。这项建议的目的是研究最近发现的I型赖氨酰-tRNA合成酶的结构/功能关系。主要目标包括：i)确定I类和II类赖氨酸-tRNA合成酶如何识别和区分赖氨酸和赖氨酸类似物。Ii)确定在体外和体内决定赖氨酸tRNA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)。这反过来将为开发专门针对I类赖氨酰-tRNA合成酶的治疗药物提供一个框架。

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.