Molecular Basis of Plasminogen-Streptokinase Interaction

描述(申请人提供)：纤溶酶原激活是 纤溶事件，对短期战略具有重要意义 治疗急性溶栓性疾病。纤溶酶原激活也起到了作用 在与肿瘤生长和转移相关的细胞迁移中发挥关键作用 阿尔茨海默病与相关脑出血及某些致病因素 入侵。链激酶是一种细菌蛋白，是一种纤溶酶原激活剂。 广泛用于临床治疗心肌梗死等 凝血障碍。与组织型纤溶酶原激活剂和尿激活酶不同， 链激酶不是一种蛋白酶。链激酶和纤溶酶原形成一种 非共价复合体，它具有蛋白水解性，并能转化其他 纤溶酶原分子转化为纤溶酶，导致纤溶。 在此之前，我们确定了催化域的晶体结构 纤溶酶原和纤溶酶与链激酶的结构。而这些 结构为纤溶酶原激活提供了重要的洞察力 链激酶和纤溶酶原之间的相互作用，也提出了新的 关于纤溶酶原链激酶的详细作用机制的质疑 复合体激活其他纤溶酶原分子，并关于调节 纤溶酶原由多种效应器激活。当前应用程序 建议解决有关非蛋白水解性激活机制的问题 纤溶酶原中的纤溶酶原：链激酶复合体，相互作用 底物纤溶酶原与激活剂的复合体及其相互作用 纤溶酶原激活及其某些生理/病理效应 使用诱变和X射线结晶学方法。

DESCRIPTION (provided by applicant): Plasminogen activation is the central event in fibrinolysis, which is of importance to the strategy of short term treatments of acute thrombolytic disorders. Plasminogen activation also plays critical roles in cell migration related to tumor growth and metastasis, Alzheimer's disease and related cerebral hemorrhage and some pathogenic invasions. Streptokinase, a bacterial protein, is a plasminogen activator widely used in the clinical treatment of myocardial infarction and other clotting disorders. Unlike tissue plasminogen activator and urokinase, streptokinase is not a protease. Streptokinase and plasminogen form a non-covalent complex, which is proteolytically active and converts other plasminogen molecules to plasmin leading to fibrinolysis. Previously, we determined the crystal structures of the catalytic domains of plasminogen and plasmin and the structure of streptokinase. While these structures have provided significant insight into the plasminogen activation and interactions between streptokinase and plasminogen, they also raise new questions about the detailed mechanisms by which the plasminogen:streptokinase complex activates other plasminogen molecules and about the regulation of plasminogen activation by a variety of effectors. The current application proposes to address questions on the mechanism of nonproteolytic activation of plasminogen in the plasminogen:streptokinase complex, the interaction of the substrate plasminogen with the activator complex and interactions between plasminogen activation and some of its physiological/pathological effectors using mutagenesis and x-ray crystallographic approaches.