Structural aspects of urokinase receptor in vascular biology

血管生物学中尿激酶受体的结构方面

• 批准号: 7178573
• 负责人: Mingdong Huang
• 金额: $ 38.25万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-15 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7178573
• 关键词: Adhesives; Alzheimer' s Disease; Binding; Biological Process; Biology; Blood Vessels; Cell Adhesion; Cell Surface Receptors; Cellular biology; Chemotaxis; Classification; Coagulation Process; Complex; Cytolysis; Data Collection; Drosophila genus; Enzyme Precursors; Epitopes; Fab Immunoglobulins; Future; G Protein-Coupled Receptor Genes; Glycoproteins; Goals; HIV-1; Human; Infection; Inflammation; Integrins; Length; Ligands; Mediating; Methods; Modeling; Molecular; Monoclonal Antibodies; Multiple Sclerosis; Nature; Neoplasm Metastasis; Pathologic; Pathologic Processes; Peptides; Physiological; Plasminogen; Play; Pliability; Preparation; Prevention; Principal Investigator; Production; Protease Domain; Proteins; Publishing; Reagent; Recombinant Proteins; Recombinants; Research Personnel; Resolution; Roentgen Rays; Role; Science; Signal Transduction; Solid; Structure; Study Section; Surface; System; Techniques; Testing; Therapeutic; Tumor Cell Invasion; Urokinase; Urokinase Plasminogen Activator Receptor; Vascular Diseases; Vitronectin; X ray diffraction analysis; X-Ray Crystallography; X-Ray Diffraction; angiogenesis; base; cell motility; chemical synthesis; computerized data processing; conformational alteration; design; mutant; neointima formation; programs; protein expression; protein protein interaction; receptor; receptor binding; small molecule; stem; tool; tumor

DESCRIPTION (provided by applicant): Urokinase plasminogen activator (uPA) together with its cell surface receptor (uPAR) mediates surface-bound plasminogen activation and has been recognized to play essential roles in several biological processes important in vascular biology, including clot lysis, cell adhesion, cell migration, inflammation, signal transduction, angiogenesis, and chemotaxis. Therefore, the study of this system will be critical to understand the causes, prevention, and treatment of vascular disorders and diseases including tumor invasion, tumor metastasis, neointima formation, infection with human immunodeficiency virus-1 (HIV-1), Alzheimer disease, and multiple sclerosis. The molecular basis for these broad physiological and pathophysiological roles of uPAR/uPA system stems from uPAR's capability to interact with many diverse ligands, e.g., uPA, vitronectin, integrins (31, 32, 33), LRP, GPCR, and the dynamic conformational changes caused by these protein-protein interactions. The principal investigator's recent results (Huai, et al. "Structure of Human Urokinase Plasminogen Activator in Complex", Science, in press, 2006) suggest conformational flexibility of uPAR. The goal of this proposal is to systematically study the structural basis and the dynamic nature of the interactions between uPAR and its ligands. The principal investigator proposes to study the structures of soluble uPAR (suPAR) (aim 1), suPAR in complex with vitronectin (aim 2), suPAR in complex with full- length uPA (aim 3), and to compare and analyze the structures of suPAR and suPAR-ligand complexes (aim 4). Protein X-ray crystallography will be the main tool to study these protein-protein interactions, but other common molecular and cell biology techniques will also be used. The principal investigator has established methods to generate needed reagents and has made several preliminary suPAR-ligand crystals, providing a solid basis for these proposed studies. These systematic structural studies of uPAR and its complexes with physiologically important uPA forms and vitronectin will understand the dynamic interactions between uPAR and its ligands, identify unanimously the binding determinants on the receptor and the ligands that confer therapeutic accessibility, and provide a framework for future design and optimization of small molecular antagonists to regulate these protein-protein interactions and to intervene the pathologic consequences resulting from these interactions.

描述（由申请人提供）：尿激酶纤溶酶原激活剂（uPA）与其细胞表面受体（uPAR）一起介导表面结合纤溶酶原激活，并已被认为在血管生物学中重要的几个生物过程中发挥重要作用，包括血栓溶解、细胞粘附、细胞迁移、炎症、信号转导、血管生成和趋化性。因此，对该系统的研究对于了解血管疾病和疾病的原因、预防和治疗至关重要，包括肿瘤侵袭、肿瘤转移、新内膜形成、人类免疫缺陷病毒-1（HIV-1）感染、阿尔茨海默病和多发性硬化症。 uPAR/uPA 系统这些广泛的生理和病理生理作用的分子基础源于 uPAR 与许多不同配体相互作用的能力，例如 uPA、玻连蛋白、整联蛋白 (31、32、33)、LRP、GPCR，以及这些蛋白质-蛋白质相互作用引起的动态构象变化。主要研究者的最新结果（Huai 等人，“复合物中人尿激酶纤溶酶原激活剂的结构”，《科学》，出版，2006 年）表明了 uPAR 的构象灵活性。该提案的目标是系统地研究uPAR与其配体之间相互作用的结构基础和动态性质。主要研究者计划研究可溶性uPAR (suPAR)（目标1）、suPAR与玻连蛋白复合物的结构（目标2）、suPAR与全长uPA复合物的结构（目标3），并比较和分析suPAR和suPAR-配体复合物的结构（目标4）。蛋白质 X 射线晶体学将成为研究这些蛋白质-蛋白质相互作用的主要工具，但也将使用其他常见的分子和细胞生物学技术。主要研究人员已经建立了生成所需试剂的方法，并制备了几种初步的 suPAR-配体晶体，为这些拟议的研究提供了坚实的基础。这些对 uPAR 及其复合物与生理上重要的 uPA 形式和玻连蛋白的系统结构研究将了解 uPAR 及其配体之间的动态相互作用，一致确定受体和配体上赋予治疗可及性的结合决定因素，并为未来设计和优化小分子拮抗剂提供框架，以调节这些蛋白质-蛋白质相互作用并干预由 这些相互作用。