变异链球菌致病相关蛋白的结构与功能研究

Streptococcus mutans is an opportunistic pathogen. As a member of the human oral flora, it has been implicated as a primary cause of dental caries and a key pathogen of infective endocarditis. To persist in the oral cavity, S. mutans must be able to tolerate rapid environmental fluctuations and exposure to various toxic chemicals, and to adapt and respond to environmental stresses. The virulence factors of S. mutans such as carbohydrate metabolism, tolerance and production of acids, synthesis of cells polysaccharide and adhesion ability contribute to dental caries. Up to now, the infection routes and the pathogenesis has not yet been answered satisfactorily. .In this project, 11 proteins that are related with the pathogenesis of S. mutans were selected as research targets. They contribute to the human caries directly or indirectly. We try to determine their crystal structures. The information provided by the crystal structures of the pathogenesis-related proteins will help to further elucidate their biological functions in the infections of S. mutans. At the same time, we will construct the mutant strains of S. mutans (inactivation of one or more of these genes) based on the structural information, so as to observe the changes of their biological feathers, to understand the interaction between the bacterium and the host, and to confirm the relationship between the protein structure and the protein functions. All of these research works will provide enough theoretical basis for developing new generations of anti-S. mutans drugs and vaccines.

变异链球菌（Streptococcus mutans）是龋病的主要致病菌，不同龋指数患者口腔变异链球菌的体外致龋能力不同，提示不同菌株的致龋性是不同的，而致龋性主要是通过其毒力因子来完成的，相关基因的突变导致变异链球菌的致龋性发生改变，但其感染途径和致病机制至今尚未得到完满的解答。本研究选择11种与变异链球菌产糖、产酸、耐酸和黏附等相关的蛋白，这些蛋白与龋病的发生、发展有直接或间接的关系。通过解析其晶体结构，从结构生物的角度阐明这些蛋白结构与生物学功能之间的关系。并基于高分辨率晶体所提供的结构信息，构建相应基因灭活的突变菌株，观察菌株生物学特性的改变，更好地了解这些蛋白与宿主之间的相互作用，确定其生物学功能。为进一步阐明变异链球菌的致病机制和研制新一代抗变异链球菌的药物和疫苗提供理论基础。

摘要：龋齿是所有人易发的齿科疾病，不同程度地影响着人们的日常生活质量。变异链球菌（Streptococcus mutans）是龋病的主要致病菌，具有广泛的适应能力，可以持续存在于口腔中。研究发现，不同龋指数患者口腔变异链球菌的体外致龋能力不同，提示不同菌株的致龋性是不同的，而致龋性主要是通过其毒力因子来完成的，但其感染途径和致病机制至今还未得到完满的解答。在本研究中，按计划完成了课题计划书中的大部分内容，通过对芳香族氨基酸氨基转移酶和核糖基高半胱氨酸酶的晶体结构解析，从结构生物的角度阐明这些蛋白结构与生物学功能之间的关系，更好地了解这些蛋白与宿主之间的相互作用，确定其生物学功能。此外，基于这些蛋白的晶体结构，可以进行抗变异链球菌药物的理性设计。对阐明变异链球菌的致病机制和研制新一代抗变异链球菌的药物提供了理论基础。