Structure of copper transporting ATPases

铜转运ATP酶的结构

• 批准号: 7192550
• 负责人: Matthew H Sazinsky
• 金额: $ 1.74万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7192550
• 关键词: ATP phosphohydrolase; Address; Antineoplastic Agents; Binding; Binding Sites; Biochemistry; Cadmium; Carboplatin/Cisplatin; Catalytic Domain; Cations; Cell membrane; Cisplatin; CopA ATPase; Copper; Disease; Goals; Heavy Metals; Hepatolenticular Degeneration; Homeostasis; Homologous Gene; Human; Inherited; Ions; Lead; Membrane; Menkes Kinky Hair Syndrome; Metal Ion Binding; Metals; Modeling; Molecular; Molecular Chaperones; Mutation; Organism; Platinum; Proteins; Resistance; Specificity; Structure; System; Vanadates; Zinc; analog; antitumor drug; base; copper-transporting ATPase; drug efficacy; improved; insight; nervous system disorder

DESCRIPTION (provided by applicant): All organisms have molecular systems that function to maintain metal ion homeostasis. The P1B-type ATPases are membrane-bound ion transporters responsible for the efflux of heavy metals and are essential for controlling the cellular levels of beneficial metals like copper and zinc and removing toxic ones like cadmium and lead. Malfunctioning copper ATPases in humans result in inherited neurological disorders like Menkes' syndrome and Wilson's disease. The Wilson ATPase has also been implicated in promoting resistance to the anticancer drugs cisplatin and carboplatin. The mechanisms of metal transport across membranes by these ATPases are not well understood. The goal of this proposal is to crystallize and determine the structure of CopA from A. fulgidus, a well characterized copper transporting P1B-type ATPase with strong identity to both the Menkes' and Wilson's proteins. Structural characterization of CopA will help to elucidate the mechanism of copper transport across cell membranes and will provide new insight into its human homologues that may be relevant to the treatment of disease and the improvement of platinum based antitumor drugs. The structure of a P1 B-type ATPase will be the first of its kind.

描述（由申请人提供）： 所有生物体都具有维持金属离子稳态的分子系统。 P1B 型 ATP 酶是膜结合离子转运蛋白，负责重金属的流出，对于控制铜和锌等有益金属的细胞水平以及去除镉和铅等有毒金属至关重要。人类铜 ATP 酶功能障碍会导致遗传性神经系统疾病，如门克斯综合征和威尔逊病。 Wilson ATP 酶还与促进抗癌药物顺铂和卡铂的耐药性有关。这些 ATP 酶跨膜金属转运的机制尚不清楚。该提案的目标是结晶并确定来自 A. fulgidus 的 CopA 的结构，CopA 是一种经过充分表征的铜转运 P1B 型 ATP 酶，与 Menkes 蛋白和 Wilson 蛋白具有很强的同一性。 CopA 的结构表征将有助于阐明铜跨细胞膜转运的机制，并将为其人类同系物提供新的见解，这可能与疾病的治疗和铂类抗肿瘤药物的改进相关。 P1 B 型 ATP 酶的结构将是同类中的第一个。