ABC Transport Components: Structures and Functions

描述（由申请人提供）：本研究计划的长期目标是研究细菌ATP结合盒型转运系统（ABC转运蛋白）及其蛋白组分的结构和功能。结构分析，使用X射线晶体学技术，将集中在两个组件，包括几个结合蛋白，赋予溶质特异性的转运蛋白和趋化性，以及位于细胞质表面的ATP酶水解亚基的同源二聚体的膜。具有结合的二肽的二肽结合蛋白的结构可以在开发利用转运体的广泛特异性用于递送和生物活性的抗菌药物（包括不渗透的肽模拟药物）中提供富有成效的线索。将尝试在过渡状态下结晶整个ABC转运蛋白。利用晶体学，诱变和生物化学技术，蛋白质配体识别功能的基本调查也将继续进行。转运过程通过维持细胞内环境的相对恒定性和调节代谢活动所需的各种物质的进入和离开来在细胞的生命中执行重要功能。趋化性对于微生物的生存（和控制）是重要的，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、蛋白分泌、抗原呈递、药物和抗生素抗性、细菌致病和孢子形成。几种人类疾病已被追溯到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，因此赋予病原菌抗生素抗性或细胞防御因子的试剂对公共卫生的威胁越来越大。

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.