Determination of the SAG Binding Motif on AgI/II of Streptococcus Mutans

描述（由申请人提供）：细菌附着于宿主组织是可能导致临床表现感染的过程中的关键第一步。细菌感染可以看作是微生物和宿主之间的一场战斗。这种主要活动开始于细菌试图附着并在宿主体内定居。细菌的表面成分在这里起着重要的作用。在金黄色葡萄球菌中，所有表面蛋白的配体结合区都利用一个保守的DEv-IgG折叠，通过修饰残基和结构域的取向与各种细胞外基质分子结合。我们假设每个细菌物种都通过一个明确的粘附基序发展了自己的粘附系统。为了解决这一假设，我们建议鉴定抗原l/ll （Agl/ll）的唾液凝集素糖蛋白（SAG）粘附基元，抗原l/ll是变形链球菌的表面蛋白粘附素，是一种已知的龋齿病原。现在已知Agl/ll与SAG相互作用的途径是通过gp340介导的，gp340是一种含有富含清除率受体半胱氨酸（SRCR）结构域的糖蛋白。为了明确粘附基序，我们将：1)确定Agl/ll的AVP区域的晶体结构；2)绘制和表征Agl/ll结构域与gp340结构域的相互作用；3)建立Agl/ll-gp340结合模型，识别结合基序。Agl/ll的SAG粘附基序的鉴定将促进基于结构的小分子或肽抑制剂的药物设计，用于抗感染治疗或开发候选龋齿疫苗。

DESCRIPTION (provided by applicant): Bacterial attachment to host tissue is a critical first step in a process that may lead to clinically manifested infections. A bacterial infection can be regarded as a battle between the microbe and the host. This primary campaign starts with the bacteria's attempt to adhere and colonize the host. It is here that the surface components on bacteria play an important role. In Staphyloccocous aureus, the ligand-binding regions of all the surface proteins utilize a conserved DEv-IgG fold to bind to various extracellular matrix molecules through modification of residues and orientation of domains. We hypothesize that every bacterial species has developed its own system of adherence through a definitive adherence-motif. To address this hypothesis, we propose to identify the salivary agglutinin glycoprotein (SAG) adherence motif of Antigen l/ll (Agl/ll), a surface protein adhesin of Streptococcus mutans that is a known etiological agent of dental caries. The means by which Agl/ll interacts with SAG is now known to be mediated through gp340, a glycoprotein that contains scavenger receptor cystein rich (SRCR) domains. To identify the adherence-motif specifically, we will: 1) Determine the crystal structure of the AVP region of Agl/ll; 2) Map and characterize the interaction between the Agl/ll domains and gp340 domains; and finally 3) Create an Agl/ll-gp340 binding model and identify the binding-motif. The identification of the SAG adherence-motif of Agl/ll will facilitate structure-based drug design of either a small molecule or a peptide inhibitor for use in anti-infection therapy or for development of caries vaccine candidates.