Solution NMR Studies of an ATP-Binding Cassette

ATP 结合盒的溶液 NMR 研究

• 批准号: 6648066
• 负责人: Chunyu Wang
• 金额: $ 4.64万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6648066
• 关键词: active sites; adenosine diphosphate; adenosine triphosphate; biological signal transduction; catalyst; conformation; cystic fibrosis; membrane transport proteins; multidrug resistance; nuclear magnetic resonance spectroscopy; postdoctoral investigator; protein folding; protein structure function

DESCRIPTION (provided by applicant): The ATP-binding cassette (ABC) is the signature module of the ABC transporter superfamily. ABC transporters comprise a significant percentage of all non-viral genomes and transport a variety of important cargos, including ions, amino acids, lipids, sugars and proteins, across cell and organelle membranes. The ABC transporters are associated with a number of diverse and critical pathologies, such as multi-drug resistance (MDR) and cystic fibrosis. ATP-binding cassettes are the energy generating motor domain of the ABC transporters but their mechanism of ATP hydrolysis and mechanochemical energy transduction is poorly understood. Recent crystallographic studies suggest that ATP-induced conformational changes in ABCs are likely to be the crucial coupling mechanism between ATP hydrolysis and solute translocation. The present fellowship proposal will apply a wide array of powerful solution nuclear magnetic resonance (NMR) techniques to delineate ATP-induced conformational and dynamic changes in the ABC domain (MJ1267) of the branched amino acid transporter from a hyperthermophilic archaebacterium. Similar studies will be carried out in a variety of mutants to establish the relationship between ATP-induced conformational changes, the mechanism of ATP-catalysis and molecular etiology of important diseases. Detailed structural and dynamic information gleaned from the proposed studies will broaden our fundamental understanding of ATP-binding cassette function and contribute essential knowledge and tools to the structure-based drug design for cystic fibrosis.

描述(申请人提供)：三磷酸腺苷结合盒(ABC)是ABC转运体超家族的签名模块。ABC转运蛋白在所有非病毒基因组中占相当大的比例，它通过细胞膜和细胞器膜运输各种重要的货物，包括离子、氨基酸、脂类、糖和蛋白质。ABC转运蛋白与许多不同和关键的病理过程有关，如多药耐药(MDR)和囊性纤维化。三磷酸腺苷结合盒是ABC转运蛋白的能量产生马达结构域，但其对三磷酸腺苷的水解和机械力化学能量转导的机制知之甚少。最近的结晶学研究表明，ATP诱导的ABC构象变化可能是ATP水解和溶质转运之间的关键耦合机制。目前的奖学金提案将应用广泛的强大的溶液核磁共振(NMR)技术来描述ATP诱导的来自高温考古细菌的分支氨基酸转运蛋白ABC结构域(MJ1267)的构象和动态变化。类似的研究将在各种突变体中进行，以建立ATP诱导的构象变化、ATP催化机制和重要疾病的分子病因学之间的关系。从拟议的研究中收集到的详细的结构和动态信息将扩大我们对ATP结合盒功能的基本理解，并为囊性纤维化的基于结构的药物设计提供必要的知识和工具。