ABC Transport Components: Structures and Functions

描述(申请人提供)：本研究计划的长期目标是研究细菌三磷酸腺苷结合盒类型转运系统(ABC转运体)的结构和功能及其蛋白质组分。使用X射线结晶学技术的结构分析将集中在两个组分上，包括几个赋予转运蛋白和趋化作用的溶质专一性的结合蛋白，以及位于细胞质表面的ATPase水解亚单位的同源二聚体。结合了二肽的二肽结合蛋白的结构可能为开发抗菌药物(包括不可用的测肽法药物)提供富有成效的线索，从而利用转运蛋白的广泛特异性来传递和发挥生物活性。将尝试结晶处于过渡状态的整个ABC转运体。利用结晶学、诱变和生化技术，还将对蛋白质-配体识别的特征进行基础研究。运输过程通过维持细胞内环境的相对稳定和调节新陈代谢活动所必需的各种物质的进出，在细胞的生命中发挥着至关重要的作用。趋化性对于微生物的生存(和控制)很重要，因为与环境的相互作用在很大程度上取决于对刺激的反应能力。除了主动转运外，ABC转运蛋白还参与信号转导、蛋白质分泌、抗原递呈、药物和抗生素耐药性、细菌发病和孢子形成。一些人类疾病被追溯到ABC蛋白，包括囊性纤维化、高胰岛素血症和黄斑营养不良。由于细菌ABC转运蛋白的几种底物也是毒力因子，赋予病原菌抗生素耐药性或细胞防御因子的物质对公共健康构成越来越大的威胁。

DESCRIPTION (provided by applicant): The long-range objective of this research program is to study the structure and function of bacterial ATP-binding cassette-type transport systems (ABC transporters) and their protein components. Structural analysis, using X-ray crystallographic technique, will focus on two components, including several binding proteins that confer the solute specificity of the transporter and chemotaxis as well and the homodimer of the ATPase-hydrolyzing subunits located at the cytoplasmic surface of the membrane. The structures of the dipeptide-binding protein with bound dipeptides may provide fruitful leads in the development of antibacterial drugs (including impermeant peptidomimetric drugs) that exploit the broad specificity of the transporter for delivery and bioactivity. Crystallization of an entire ABC transporter in a transition state will be attempted. Using crystallographic, mutagenic, and biochemical techniques, fundamental investigation of the features of protein-ligand recognition will also be pursued. Transport processes perform a vital function in the life of a cell by maintaining a relative constancy of the intracellular environment and regulating the entrance and exit of various substances necessary for metabolic activity. Chemotaxis is important for the survival (and control) of microorganisms since interaction with the environment depends largely on the ability to respond to stimuli. Beside active transport, the ABC transporters are also involved in signal transduction, protein secretion, antigen presentation, drug and antibiotic resistance, bacterial pathogenesis and sporulation. Several human diseases have been traced to ABC proteins, including cystic fibrosis, hyperinsulinemia, and macular dystrophy. Because several of the substrates of the bacterial ABC transporters are also virulence factors, agents that confer antibiotic resistance, or cellular defense factors on pathogenic bacteria are a growing threat to public health.