STRUCTURE OF THE NUCLEOTIDE-BINDING DOMAINS OF HUMAN COPPER-TRANSPORTING ATPASES
人铜转运ATP酶的核苷酸结合域的结构
基本信息
- 批准号:7721645
- 负责人:
- 金额:$ 0.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-03-01 至 2009-02-28
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseBindingBinding SitesBiochemicalCa(2+)-Transporting ATPaseClassComputer Retrieval of Information on Scientific Projects DatabaseCopperData CollectionDiseaseEnvironmentEnzymesFundingFutureGenesGoalsGrantHeavy MetalsHepatolenticular DegenerationHumanInborn Errors of MetabolismInstitutionLocationMenkes Kinky Hair SyndromeMetabolismMutationN DomainNucleotidesProcessPropertyProteinsPublishingRegulationResearchResearch PersonnelResolutionResourcesSolutionsSourceStructureSurfaceTransmembrane TransportUnited States National Institutes of HealthVariantWalkersWilson disease proteincopper-transporting ATPasedisease-causing mutationdomain mappinghuman tissuemutantthree dimensional structure
项目摘要
This subproject is one of many research subprojects utilizing the
resources provided by a Center grant funded by NIH/NCRR. The subproject and
investigator (PI) may have received primary funding from another NIH source,
and thus could be represented in other CRISP entries. The institution listed is
for the Center, which is not necessarily the institution for the investigator.
The goal of this project is to solve the structures of the nucleotide binding domains of the two human copper-transporting ATPases, Wilson disease associated protein and Menkes disease associated protein and to elucidate conformational changes caused in the domains by ATP binding. The copper-transporting ATPases belong to a distinct and poorly studied class of membrane transport enzymes (Lutsenko et al., 2002) and are essential for copper-metabolism in human tissues. Mutations in the ATP7A and ATP7B genes encoding these proteins result in severe hereditary metabolic disorders. No high-resolution structure of a heavy metal transporting ATPase has been published to date.The structures of the nucleotide binding domains will be solved in the nucleotide-free and ATP-bound forms. Location of the ATP -binding site in the three-dimensional structure of the domains will be determined. Conformational changes taking place upon ATP binding will be studied in the context of the catalytic cycle of the P-type ATPases, with the emphasis on unique features separating heavy-metal transporting ATPases from well studied Ca2+-ATPase. The differences in the three-dimensional structures of the nucleotide binding domains of Wilson disease and Menkes disease proteins associated with non-homologous regions of primary structure will be determined. This project will also provide groundwork for the future studies of the structural effects of disease-causing mutations in the copper-transporting ATPases, for solving the structures of the larger domains of Wilson and Menkes disease proteins and mapping the domain-domain interaction surfaces. To date the structure of the N-nucleotide-binding domain of the Wilson disease ATPase (WNABD) comprising residues 1036-1196 has been solved in ATP bound form (Dmitriev et al., 2006). Data collection and processing for structure determination of two disease-causing mutant variants of the N-domain (E1064A and H1069A) is in progressReferences 1. Dmitriev, O., Tsivkovskii, R., Abildgaard, F., Morgan, C. T., Markley, J. L., and Lutsenko, S. (2006) Solution structure of the N-domain of Wilson disease protein: Distinct nucleotide-binding environment and effects of disease mutations Proc. Natl. Acad. Sci. U. S. A 103, 5302-5307. 2. Lutsenko, S., Efremov, R. G., Tsivkovskii, R., and Walker, J. M. (2002) Human copper-transporting ATPase ATP7B (the Wilson's disease protein): biochemical properties and regulation J. Bioenerg. Biomembr. 34, 351-362.
这个子项目是众多研究子项目之一
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('OLEG Y DMITRIEV', 18)}}的其他基金
STRUCTURE OF THE NUCLEOTIDE-BINDING DOMAINS OF HUMAN COPPER-TRANSPORTING ATPASES
人铜转运ATP酶的核苷酸结合域的结构
- 批准号:
7954614 - 财政年份:2009
- 资助金额:
$ 0.18万 - 项目类别:
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