THE EFFECT OF MOLECULAR TOXINS ON PROTEIN PHOSPHATASE 1 TARGETING

分子毒素对蛋白磷酸酶 1 靶向的影响

• 批准号: 7725163
• 负责人: Wolfgang Peti
• 金额: $ 12.44万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7725163
• 关键词: 3-Dimensional; Active Sites; Affect; Binding; Biochemical; Biological Factors; Cells; Complex; Computer Retrieval of Information on Scientific Projects Database; Cyanobacterium; Funding; Grant; Institution; Ligands; Localized; MSMB gene; Marines; Molecular; NMR Spectroscopy; Neurons; Okadaic Acid; Organism; Phosphoric Monoester Hydrolases; Population; Porifera; Protein phosphatase; Proteins; Research; Research Personnel; Resources; Scaffolding Protein; Source; Structural Models; Structure; Techniques; Toxin; United States National Institutes of Health; X ray spectroscopy; X-Ray Crystallography; calyculin A; dopaminergic neuron; fostriecin; inhibitor/antagonist; microcystin; molecular modeling; novel; small molecule; spinophilin; tautomycin

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. Molecular toxins are natural products that potently inhibit the catalytic activity of protein phosphatase 1 (PP1). These natural inhibitors are created by numerous organisms such as marine sponges and cyanobacteria and include okadaic acid, calyculin A, microcystins, nodularins, tautomycin and fostriecin. We want to comprehensively understand the structural and dynamical mechanisms of the tight binding of these molecular toxins to PP1. This will enable us to characterize the subtle molecular differences of the PP1 active site induced by targeting and inhibitory proteins versus small molecule molecular toxins. These 3-dimensional molecular models will enable us to fully understand the details of the PP1 active site structure. To understand the PP1 active site dynamics, and its subtle interplay of targeting protein and inhibitory ligand (molecular toxin) interactions in molecular detail, we will use a large portfolio of biochemical and biophysical techniques, especially NMR spectroscopy and X-ray crystallography, to elucidate the structures of numerous targeting proteins and molecular toxins by themselves and as PP1:targeting and PP1:molecular toxin complexes. PSP targeting proteins, such as the neuronal scaffolding protein spinophilin, target PP1 to its point of action. No structural models for these interactions exist, nor is it known how they are affected by interactions with molecular toxins. Thus, we will use the differences and similarities between the multiple PP1:toxin and PP1:targeting structures and dynamics to determine how PP1, a ubiquitous ser/thr phosphatase, is potently and selectively regulated in the cell so that novel agents, which target a particular population of phosphatases (i.e. phosphatases localized in dopaminergic neurons), can be developed.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 分子毒素是有效抑制蛋白磷酸酶 1 (PP1) 催化活性的天然产物。这些天然抑制剂由海绵和蓝细菌等多种生物体产生，包括冈田酸、花萼菌素 A、微囊藻毒素、结球菌素、互变霉素和磷霉素。我们希望全面了解这些分子毒素与 PP1 紧密结合的结构和动力学机制。这将使我们能够表征由靶向和抑制蛋白与小分子毒素诱导的 PP1 活性位点的细微分子差异。这些3维分子模型将使我们能够充分了解PP1活性位点结构的细节。为了了解 PP1 活性位点动力学及其分子细节中靶向蛋白和抑制性配体（分子毒素）相互作用的微妙相互作用，我们将使用大量的生化和生物物理技术，特别是 NMR 波谱学和 X 射线晶体学，来阐明众多靶向蛋白和分子毒素本身的结构，以及作为 PP1：靶向和分子毒素的结构。 PP1：分子毒素复合物。 PSP 靶向蛋白（例如神经元支架蛋白亲旋蛋白）将 PP1 靶向其作用点。这些相互作用的结构模型不存在，也不知道它们如何受到分子毒素相互作用的影响。因此，我们将利用多种 PP1：毒素和 PP1：靶向结构和动力学之间的差异和相似性来确定 PP1（一种普遍存在的丝氨酸/苏氨酸磷酸酶）如何在细胞中有效且选择性地受到调节，以便可以开发针对特定磷酸酶群体（即定位于多巴胺能神经元的磷酸酶）的新药物。