Study of Allosteric Proteins by NMR

通过 NMR 研究变构蛋白

• 批准号: 7856391
• 负责人: ERIK R ZUIDERWEG
• 金额: $ 16.72万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-10 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7856391
• 关键词: ATP phosphohydrolase; Binding; Biochemistry; Biophysics; Cattle; Cells; Cellular Stress; Complex; Disease; Disease Management; Funding; Generations; Gusperimus; Head; Heat-Shock Response; Homo sapiens; Human; Ligands; Link; Maps; Mediating; Molecular; Molecular Chaperones; Molecular Conformation; NMR Spectroscopy; Nucleotides; Organism; Postdoctoral Fellow; Proteins; Regulation; Relative (related person); Research; Research Personnel; Residual state; Signal Transduction; Site; Solutions; Spectrum Analysis; Structural Biologist; Structure; Students; Substrate Domain; Testing; Thermus thermophilus; Work; base; design; graduate student; improved; insight; malignant breast neoplasm; programs; protein folding; research study; three dimensional structure; trafficking

DESCRIPTION (provided by applicant): Hsp70 (heat shock 70 kDa) chaperone proteins are central to protein folding, refolding, and trafficking in organisms ranging from Archae to Homo Sapiens, both at normal and at stressed cellular conditions. Hsp70's (re) fold proteins via binding and release cycles at the substrate-binding domain involving conformational changes caused by ATP and ADP binding at the nucleotide-binding domain. This remote regulation mechanism is called allostery. Recently, Hsp70's have been linked to diseases such as breast cancer. Modulation of the allosteric mechanism of the Hsp70's with small compounds may form an avenue to treat these diseases. We propose to investigate the mechanism in detail by determining the solution conformations of 60 kDa Hsp70 protein constructs, containing both nucleotide- and substrate-binding domains and their complexes with co-chaperones in different liganded states. We will investigate the molecular basis for the action of the first generation of Hsp70 modulating compounds. The combined insights gained will aid in the design of improved compounds for the treatment of cell-management diseases. The research will be carried out using ultra-high field nuclear magnetic resonance spectroscopy.

描述(申请人提供)：HSP70(热休克70 kDa)伴侣蛋白是蛋白质折叠、重折叠和运输从古生物到智人的中心，无论是在正常的细胞条件下还是在应激的细胞条件下。S(Re)通过底物结合区的结合和释放循环折叠蛋白质，涉及核苷酸结合区的三磷酸腺苷和腺苷二磷酸结合引起的构象变化。这种远程调节机制被称为变构。最近，热休克蛋白70的S基因被认为与乳腺癌等疾病有关。用小分子化合物调节热休克蛋白70‘S的变构机制可能是治疗这些疾病的一条途径。我们建议通过测定60 kDa Hsp70蛋白结构物的溶液构象来详细研究这一机制，这些结构物同时包含核苷酸和底物结合结构域，以及它们与处于不同连接状态的辅助伴侣的复合体。我们将研究第一代Hsp70调节化合物作用的分子基础。所获得的综合见解将有助于设计用于治疗细胞管理性疾病的改进化合物。这项研究将使用超高场核磁共振波谱进行。