Study of Allosteric Proteins by NMR

描述（由申请人提供）：在正常和应激细胞条件下，Hsp70（热休克70 kDa）分子伴侣蛋白对从古细菌到智人的生物体中的蛋白质折叠、重折叠和运输至关重要。热休克蛋白70的（再）折叠蛋白通过结合和释放循环在底物结合域涉及构象变化引起的ATP和ADP结合在核苷酸结合域。这种远程调节机制被称为变构。最近，Hsp70与乳腺癌等疾病有关。用小化合物调节Hsp70的变构机制可能形成治疗这些疾病的途径。我们建议详细调查的机制，通过确定60 kDa的热休克蛋白70蛋白质的结构，包含核苷酸和底物结合域和它们的复合物在不同的配体状态的辅分子伴侣的溶液构象。我们将研究第一代热休克蛋白70调节化合物的作用的分子基础。所获得的综合见解将有助于设计用于治疗细胞管理疾病的改进化合物。这项研究将使用超高场核磁共振光谱进行。

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.