STRUCTURAL ANALYSIS OF WILSON DISEASE ATPASE

威尔逊病ATP酶的结构分析

• 批准号: 8361162
• 负责人: OLEG Y DMITRIEV
• 金额: $ 0.16万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361162
• 关键词: ATP phosphohydrolase; ATP7A protein; Activity Cycles; Binding; Binding Sites; Carrier Proteins; Cell membrane; Cells; Connective Tissue; Copper; Disease; Drug Metabolic Detoxication; Drug resistance; Endocrine; Enzymes; Event; Funding; Grant; Hepatolenticular Degeneration; Human body; Individual; Malignant Neoplasms; Maps; Menkes Kinky Hair Syndrome; Metabolic Diseases; Metabolism; Molecular; Molecular Structure; Motion; Mutation; National Center for Research Resources; Neurons; Nuclear Magnetic Resonance; Pathway interactions; Pharmaceutical Preparations; Platinum; Principal Investigator; Process; Protein Dynamics; Proteins; Research; Research Infrastructure; Resistance; Resources; Respiration; Solutions; Source; Structure; Techniques; United States National Institutes of Health; Work; base; copper-transporting ATPase; cost; design; disease-causing mutation; improved; inhibitor/antagonist; insight; protein structure

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Copper is required for the activity of many enzymes involved in respiration, neuron function, formation of connective tissue, endocrine processes, and radical detoxification in the human body. Wilson disease ATPase and Menkes disease ATPase regulate copper concentration in the cell and deliver copper to biosynthetic pathways. These proteins are targets of many mutations that cause severe metabolic disorders. Importantly, Wilson and Menkes ATPases are involved in cancer resistance to platinum- based chemotherapeutic drugs. To understand the critical steps in the activity cycle of the copper ATPases, we will investigate the structure, molecular motions and interactions of the isolated domains, or functional modules, of the Wilson and Menkes proteins using multidimensional Nuclear Magnetic Resonance (NMR), a technique uniquely suited for studying protein structure and dynamics in solution. We will trace the sequence of molecular events involved in substrate binding by copper-transporting ATPases and analyze the structural basis of several frequent disease causing mutations. To trace the pathway of copper in Wilson and Menkes disease ATPases, we will attempt to map the copper-binding site in the cell membrane. This work is expected to improve the understanding of an important class of transport proteins and provide a new insight into the molecular basis of the disorders of copper metabolism. Structures of the individual domains of Wilson and Menkes ATPase will facilitate design of the new inhibitors and modulators of these enzymes, which may help to overcome certain types of drug resistance in cancer.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 许多参与呼吸，神经元功能，结缔组织的形成，内分泌过程以及人体中的根治排毒的酶的活性是必需的。 威尔逊疾病ATPase和Menkes病ATPase调节细胞中的铜浓度，并将铜输送到生物合成途径。 这些蛋白质是导致严重代谢性疾病的许多突变的靶标。重要的是，威尔逊和门克斯ATPases参与了对铂基化学治疗药物的抗癌。为了了解铜ATPases活性周期中的关键步骤，我们将使用多维核磁共振（NMR）（一种技术独特的适合研究蛋白结构和溶液中的动力学。我们将通过铜运输ATPases来追踪与底物结合所涉及的分子事件的序列，并分析几种常见疾病引起突变的结构基础。 为了追踪Wilson和Menkes病ATPases中铜的途径，我们将尝试绘制细胞膜中的铜结合位点。预计这项工作将提高对重要类传输蛋白的理解，并为铜代谢疾病的分子基础提供新的见解。 Wilson和Menkes ATPase各个领域的结构将促进这些酶的新抑制剂和调节剂的设计，这可能有助于克服癌症中某些类型的耐药性。