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.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 铜是人体呼吸、神经元功能、结缔组织形成、内分泌过程和自由基解毒等多种酶活性所必需的。威尔逊病ATPase和门克斯病ATPase调节细胞中铜的浓度，并将铜输送到生物合成途径。这些蛋白质是许多突变的目标，这些突变会导致严重的代谢紊乱。重要的是，威尔逊和门克斯ATPase参与了癌症对铂类化疗药物的耐药性。为了了解铜ATPase活性周期中的关键步骤，我们将使用多维核磁共振(NMR)来研究Wilson和Menkes蛋白质的孤立结构域或功能模块的结构、分子运动和相互作用。多维核磁共振是一种专门适合研究蛋白质在溶液中的结构和动力学的技术。我们将追踪铜转运ATPase与底物结合的分子事件序列，并分析几种常见致病突变的结构基础。为了追踪铜在肝豆状核变性和门克斯病ATPase中的途径，我们将尝试定位细胞膜上的铜结合部位。这项工作有望提高对一类重要转运蛋白的认识，并为铜代谢紊乱的分子基础提供新的见解。威尔逊和门克斯ATPase各个结构域的结构将有助于设计这些酶的新抑制剂和调节剂，这可能有助于克服癌症中某些类型的耐药性。