Molecular Basis of Plasminogen-Streptokinase Interaction

描述（由申请人提供）：纤溶酶原激活是 纤溶事件，这对短期策略具有重要意义 急性血栓溶解性疾病的治疗。纤溶酶原激活也起作用 在与肿瘤生长和转移相关的细胞迁移中发挥关键作用， 阿尔茨海默病和相关的脑出血和一些致病性 入侵链激酶是一种细菌蛋白，是一种纤溶酶原激活剂 广泛应用于临床治疗心肌梗塞等 凝血障碍与组织纤溶酶原激活剂和尿激酶不同， 链激酶不是蛋白酶。链激酶和纤溶酶原a型 非共价复合物，其具有蛋白水解活性并将其他 纤溶酶原分子转化为纤溶酶，导致纤维蛋白溶解。 以前，我们确定了催化结构域的晶体结构， 纤溶酶原和纤溶酶以及链激酶的结构。虽然这些 结构提供了纤溶酶原激活的重要见解 以及链激酶和纤溶酶原之间的相互作用，它们也引起了新的 关于纤溶酶原：链激酶 复合物激活其他纤溶酶原分子， 纤溶酶原激活的各种效应。当前应用程序 建议解决非蛋白水解激活机制的问题， 纤溶酶原：链激酶复合物中的纤溶酶原， 底物纤溶酶原与激活剂复合物的相互作用 纤溶酶原激活及其某些生理/病理效应物 使用诱变和X射线晶体学方法。

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.