UROKINASE-VITRONECTIN COMPLEX

尿激酶-玻连蛋白复合物

• 批准号: 7957250
• 负责人: Mingdong Huang
• 金额: $ 1.53万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7957250
• 关键词: Binding; Biological; Cell Adhesion; Cell Surface Receptors; Cell physiology; Cell surface; Chemotaxis; Complex; Computer Retrieval of Information on Scientific Projects Database; Crystallography; Disease; Extracellular Matrix; Funding; G-Protein-Coupled Receptors; G-substrate; Goals; Grant; Growth Factor; Human; Inflammation; Institution; Integrins; LDL-Receptor Related Protein 1; Ligands; Light; Malignant Neoplasms; Mediating; Molecular; Molecular Structure; Nature; Plasminogen; Plasminogen Inactivators; Play; Predisposition; Process; Publishing; Regulation; Research; Research Personnel; Resources; Role; Science; Signal Transduction; Source; Structure; Synchrotrons; System; United States National Institutes of Health; Urokinase; Vitronectin; base; design; flexibility; migration; protein protein interaction; stem

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. Urokinase plasminogen activator (uPA) together with its cell surface receptor (uPAR) mediates a variety of biological activities on cell surface including plasminogen activation, extracellular matrix (ECM) remodeling, growth factor activation and the initiation of intracellular signaling. The uPA system plays important roles in a variety of cellular functions, including cell adhesion, migration, invasion and chemotaxis. Moreover, it is implicated in several disease processes involved in cancer and inflammation. The molecular basis that underlies the pleiotropic activities of the uPA system stems from two aspects: 1) the ability of uPAR to interact with many ligands including uPA, vitronectin, integrins, low-density lipoprotein receptor-related protein, G-protein coupled receptor and others; 2) the dynamic conformational flexibility caused by these protein-protein interactions. Single-chain uPA (scuPA) that is usually inactive develops enzymatic activity upon binding with uPAR. In addition, scuPA and two-chain uPA (tcuPA) bound to uPAR differ in their susceptibility to plasminogen activator inhibitors, suggesting important differences in their structure and regulation. Several uPAR-ligand complexes have now been crystallized. One of them was published recently (Huai, et al., ¿¿¿¿¿SStructure of Human Urokinase Plasminogen Activator in Complex with its Receptor¿¿¿¿¿?, Science, 2006, 311:656-9). Our goal is to systematically study the structural basis and the dynamic nature of the interactions between uPAR and its ligands. The complex of uPAR and urokinase (uPA) has been suggested as a potential target for the anti-invasive and anti-metastatic therapy. The structural studies of these uPAR-ligand complexes will reveal the molecular structure of uPAR and the structural basis of interactions between uPAR and its ligands, which will provide a platform for the rational design of uPAR-uPA inhibitors to interrupt the pathophysiological consequences mediated by this interaction.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 尿激酶型纤溶酶原激活物（uPA）及其细胞表面受体（uPAR）在细胞表面介导多种生物学活性，包括纤溶酶原激活、细胞外基质（ECM）重塑、生长因子激活和细胞内信号传导的启动。uPA系统在多种细胞功能中起重要作用，包括细胞粘附、迁移、侵袭和趋化性。此外，它涉及癌症和炎症中涉及的几种疾病过程。uPA系统的多效性活性的分子基础来自两个方面：1）uPAR与许多配体（包括uPA、玻连蛋白、整合素、低密度脂蛋白受体相关蛋白、G蛋白偶联受体等）相互作用的能力; 2）由这些蛋白质-蛋白质相互作用引起的动态构象柔性。通常无活性的单链uPA（scuPA）在与uPAR结合后产生酶活性。此外，scuPA和双链uPA（tcuPA）结合uPAR不同的纤溶酶原激活物抑制剂的敏感性，这表明它们的结构和调节的重要差异。几种uPAR-配体复合物现已结晶。其中之一最近发表（Huai等人，人尿激酶纤溶酶原激活剂与其受体复合物的结构Science，2006，311：656-9）。我们的目标是系统地研究uPAR及其配体之间相互作用的结构基础和动力学性质。uPAR与尿激酶（uPA）的复合物已被认为是抗侵袭和抗转移治疗的潜在靶点。这些uPAR-配体复合物的结构研究将揭示uPAR的分子结构和uPAR与其配体之间相互作用的结构基础，这将为合理设计uPAR-uPA抑制剂以阻断这种相互作用介导的病理生理后果提供平台。