SOLUTION STRUCTURE AND INTERACTIONS OF TISSUE FACTOR

溶液结构和组织因子的相互作用

• 批准号: 6272529
• 负责人: PETER Farnum WRIGHT
• 金额: $ 31.46万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6272529
• 关键词: CHO cells; Escherichia coli; Saccharomyces cerevisiae; activation product; blood coagulation; chemical binding; coagulation factor VII; coagulation factor X; conformation; epidermal growth factor; fungal genetics; gene expression; genetic mapping; hemostasis; molecular biology; molecular cloning; molecular site; nuclear magnetic resonance spectroscopy; protein folding; protein purification; protein structure function; radiotracer; thromboplastin; thrombosis; yeasts

Tissue factor (TF) is a cell surface receptor responsible for initiation of the coagulation cascades. The extracellular domain of TF mediates protein-protein interactions with factor VIIa which results in enhancement of the catalytic activity of factor VIIa towards small peptidyl substrates. TF also mediated the assembly of the ternary complex with macromolecular substrates factors IX and X that is necessary for proteolytic activation of these zymogens. Structural characterization of TF, and elucidation of the molecular interactions involved in assembly of the binary complex with factor VIIa and the ternary complex with substrate, is central to understanding the underlying molecular events involved in initiation of the coagulation protease cascades. State-of-the-art multi-dimensional heteronuclear NMR methods will be used to determine the solution structure and flexibility of the extracellular domain of TF and of small domains of factor VIIa that bind to TF. NMR will also be used to map the surfaces of these domains involved in assembly of the TF-VIIa complex and in recognition of protein substrate factor X. The resulting structural knowledge will provide important new insights into the molecular recognition events that initiate thrombogenesis and may, in long term, form the basis for design of novel therapeutic agents that inhibit the TF induced coagulation associated with arterial thrombosis, septic shock and tumor metastasis.

组织因子（TF）是负责引发的细胞表面受体 凝结级联。 TF的细胞外域介导 蛋白质 - 蛋白质与因子VIIA的相互作用导致 VIIA因子对小的催化活性的增强 肽基底物。 TF还介导了三元组装 与大分子底物因子IX和X复合物是必要的 用于这些Zymogen的蛋白水解活化。 结构 TF的表征以及分子相互作用的阐明 与因子VIIA和 与底物的三元建筑综合体是理解 与凝血开始有关的基本分子事件 蛋白酶级联。 最先进的多维异核NMR 方法将用于确定解决方案结构和灵活性 TF的细胞外结构域和VIIA因子小域 与TF结合。 NMR也将用于映射这些表面 参与TF-VIIA复合体和认可的域 蛋白质底物因子X。由此产生的结构知识将 提供有关分子识别事件的重要新见解 启动血栓形成，长期可能构成设计的基础 抑制TF诱导凝结的新型治疗剂 与动脉血栓形成，化粪池休克和肿瘤转移有关。