NMR structure of peptide and protein complexes

肽和蛋白质复合物的 NMR 结构

• 批准号: 7922805
• 负责人: CAROL B. POST
• 金额: $ 16.22万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922805
• 关键词: Abbreviations; Affinity; B-Lymphocytes; Binding; Biochemical; C-terminal; Catalytic Domain; Complex; Computer-Assisted Image Analysis; Computing Methodologies; Disease; Entropy; Equilibrium; Event; Family; Financial compensation; Goals; Grant; ITAM; Individual; Ligands; Mediating; Membrane; Methods; Molecular; Motion; Peptides; Phosphatidylinositols; Phospholipase C; Phosphopeptides; Phosphorylated Peptide; Phosphorylation; Phosphotransferases; Phosphotyrosine; Play; Protein Tyrosine Kinase; Proteins; Receptors, Antigen, B-Cell; Regulation; Relaxation; Research Design; Research Personnel; Role; SH3 Domains; Signal Pathway; Signal Transduction; Signaling Protein; Site; Solutions; Spectrum Analysis; Structure; Surface Plasmon Resonance; Therapeutic Agents; base; cell transformation; design; enthalpy; flexibility; inhibitor/antagonist; molecular dynamics; molecular recognition; nuclear transfer; peptide B; peptide structure; programs; protein complex; protein function; protein protein interaction; receptor; research study; restraint; src Homology Region 2 Domain; src-Family Kinases

DESCRIPTION (provided by applicant): The major goal of this study is to increase our understanding, in terms of structure and dynamics, of the molecular mechanisms that regulate protein function in cellular signal transduction. Signaling pathways comprise numerous protein-protein interactions, and an individual protein often functions in multiple associations. Correspondingly, conformational flexibility plays an important role in molecular recognition events of protein-protein association and in the control of protein tyrosine kinase activation. NMR and computational methods will be used in this project to investigate conformational equilibrium important for recognition of Syk and Src-family kinases, and for conformational activation of Src kinase. Syk and Src-family protein tyrosine kinases are essential in B-cell signaling. Both Src family kinases and Syk family kinases are associated with several disease states and in particular with cell transformation. Detailed understanding of molecular recognition of these proteins is important for designing inhibitors and potential therapeutic agents against these diseases. A combination of NMR experiment and molecular dynamics computation will be used to determine the structure of various SH2 complexes and obtain information on protein motion related to binding and Src activation. We seek to understand: how conformational flexibility in the unbound state plays a role in determining binding; whether the large conformational change induced by binding to an interdomain region of Syk is general to recognition of this multifunctional site of Syk; what underlies entropy/enthalpy compensation in SH2 binding of flexible ligands; and how intramolecular domain contacts effect Src conformational activation.

描述（由申请人提供）：本研究的主要目标是增加我们对调节细胞信号转导中蛋白质功能的分子机制在结构和动力学方面的理解。信号通路包括许多蛋白质-蛋白质相互作用，并且单个蛋白质通常在多个关联中起作用。相应地，构象柔性在蛋白质-蛋白质缔合的分子识别事件和蛋白质酪氨酸激酶激活的控制中起着重要作用。NMR和计算方法将用于本项目中，以调查构象平衡重要的Syk和Src家族激酶的识别，并为Src激酶的构象激活。Syk和Src家族蛋白酪氨酸激酶在B细胞信号传导中是必不可少的。Src家族激酶和Syk家族激酶都与几种疾病状态相关，特别是与细胞转化相关。详细了解这些蛋白质的分子识别对于设计针对这些疾病的抑制剂和潜在治疗剂是重要的。NMR实验和分子动力学计算的组合将用于确定各种SH 2复合物的结构，并获得与结合和Src激活相关的蛋白质运动的信息。我们力求理解：在未结合状态下的构象灵活性如何在确定结合中起作用;通过结合到Syk的域间区域诱导的大的构象变化是否一般用于识别Syk的该多功能位点;在柔性配体的SH 2结合中的熵/焓补偿的基础是什么;以及分子内域接触如何影响Src构象激活。