II-型毒素抗毒素复合物的结构和功能研究

Toxin-antitoxin systems (TAs) are widespread on bacterial chromosomes and plasmids. TAs are involved in various physilogical and toxicological processes. To date, investigations into type II TAs found in E coli are scare, e.g. the YafQ-DinJ and HigB-HigA. Especially it is unclear about how their three-dimensional structures are formed and how they bind to their cognate operators. This project will focuse on a series of TA complex structures, including the YafQ-DinJ-DNA complex，HigB-HigA complex, and the HigB-HigA-DNA complex, for structural and functional study. Combined with biochemical methods and bacterial genetics techniques, this project aims to interogating how toxin ribonuclease degrades mRNA, how TA complex binds its cognate operator, and how TA complex acts as repressor playing a role in global gene regulation and auto-regulation as well. This work would unveil how TA modules are involved in bacterial stringent response with a combined experiment data. Therefore, investigating regulation of TA systems would provide vital information and strategy for combating antibiotic resistance in persister cell, benefit novel antimicrobial drug discovery.

毒素-抗毒素系统普遍存在于细菌染色体和质粒上，参与诸多细胞生理和毒理过程，与细菌生物膜形成和抗生素药耐受性有关。目前对于大肠杆菌II-型TA系统的研究还不多和不够系统，特别是它们结构和作用于DNA上的模式还不清楚，如，YafQ-DinJ和HigB-HigA等。本课题将以YafQ-DinJ-DNA复合物，HigB-HigA复合物以及HigB-HigA-DNA复合物等II-型TA复合物为研究对象，解析它们的晶体结构。同时综合利用生化和细胞遗传实验技术，从原子水平上阐述毒素降解mRNA的过程机制，解释TA复合物作为转录抑制因子结合DNA的作用机制，探讨TA复合物在基因调节和自我转录调节的过程机理，为进一步解释TA 系统参与其他应激反应的机制提供结构信息和实验依据。对于TA复合物的系统研究将为解决细菌的耐药性难题提供有用信息，有助于新型抗生素药物的研制和发现。

毒素-抗毒素系统普遍存在于细菌染色体和质粒上，参与诸多细胞生理和毒理过程，与细菌生物膜形成和抗生素药耐受性有关。本课题以YafQ-DinJ-DNA复合物，HigB-HigA复合物以及HigB-HigA-DNA复合物等II-型TA复合物为研究对象，解析它们的晶体结构。同时综合利用生化和细胞遗传实验技术，从原子水平上阐述毒素降解mRNA的过程机制，解释TA复合物作为转录抑制因子结合DNA的作用机制，探讨TA复合物在基因调节和自我转录调节的过程机理，为进一步解释TA 系统参与其他应激反应的机制提供结构信息和实验依。对于TA复合物的系统研究将为解决细菌的耐药性难题提供有用信息，有助于新型抗生素药物的研制和发现。