ABC Transport Components: Structures and Functions

描述（由申请人提供）：本研究项目的长期目标是研究细菌atp结合盒型转运系统（ABC转运体）及其蛋白质成分的结构和功能。结构分析，使用x射线晶体学技术，将集中在两个组成部分，包括几个结合蛋白，赋予转运蛋白的溶质特异性和趋化性，以及位于细胞膜细胞质表面的atp酶水解亚基的同二聚体。二肽结合蛋白与二肽结合的结构可能为开发抗菌药物（包括非必需肽计量药物）提供富有成效的线索，这些药物利用转运体的广泛特异性进行递送和生物活性。将尝试在过渡状态下结晶整个ABC转运体。利用晶体学、诱变和生化技术，对蛋白质配体识别特征的基础研究也将继续进行。转运过程通过维持细胞内环境的相对稳定和调节代谢活动所需的各种物质的进出，在细胞的生命中起着至关重要的作用。趋化性对微生物的生存（和控制）很重要，因为微生物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、抗原呈递、药物和抗生素耐药、细菌发病和产孢。一些人类疾病可追溯到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转运体的一些底物也是毒力因子，因此赋予致病菌抗生素耐药性的因子或细胞防御因子对公众健康的威胁越来越大。

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.