B2GPI COMPLEXES

B2GPI 复合物

• 批准号: 8170604
• 负责人: Natalia Beglova
• 金额: $ 0.27万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8170604
• 关键词: Antiphospholipid Antibodies; Antiphospholipid Syndrome; Autoantibodies; Autoimmune Process; Binding; Cell Membrane Proteins; Cell Surface Receptors; Complex; Computer Retrieval of Information on Scientific Projects Database; Crystallography; Development; Dimerization; Disease; Funding; Goals; Grant; Hemostatic function; Institution; Investigation; Pathologic; Pathology; Peptides; Phospholipids; Physiological; Plasminogen; Play; Property; Protein Binding; Proteins; Recurrence; Research; Research Personnel; Resources; Role; Source; Structure; Surface; Thrombin; Thrombosis; United States National Institutes of Health; X-Ray Crystallography; apolipoprotein E receptor 2; base; beta 2-glycoprotein I; design; inhibitor/antagonist; protein complex; tool

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. The goal of this study is to establish the structural rationale for the development of effective and safe treatments of beta2-glycoprotein I (b2GPI)-dependent antiphospholipid syndrome (APS). APS is associated with recurrent thrombosis. The pathology of APS is complex but it is clear that autoimmune antiphospholipid antibodies (aPL) directed against proteins that bind anionic phospholipid play an important role in the disease. b2GPI is a major target of aPL. b2GPI acquires pathological properties after dimerization by autoimmune antibodies that increase its local concentration, promoting interactions with other proteins and cell membranes. Blocking interactions of b2GPI with these proteins or cell surface receptors may mitigate the pathological effect of the aPL. To design an inhibitor it is important to know structural details of the binding interface in the complex. There is no structural information available for any b2GPI complexes. X-ray crystallography is used to determine the structures at the binding interfaces of b2GPI complexes with thrombin, plasminogen and ApoER2. Peptide inhibitors of complex formation will be designed and optimized based on structural information about the contact surfaces in the protein complexes. The peptide inhibitors may provide a starting point for development of non-peptide b2GPI antagonists for potential pharmacological applications, and may be used as a research tool in investigation of a physiologic role of b2GPI in hemostasis and its pathologic role in APS.

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。 本研究的目的是建立有效和安全的治疗β 2-糖蛋白I（b2 GPI）依赖性抗磷脂综合征（APS）的发展的结构原理。APS与复发性血栓形成相关。APS的病理是复杂的，但很明显，针对结合阴离子磷脂的蛋白质的自身免疫性抗磷脂抗体（aPL）在疾病中起重要作用。b2 GPI是aPL的主要目标。 b2 GPI通过自身免疫抗体二聚化后获得病理性质，增加其局部浓度，促进与其他蛋白质和细胞膜的相互作用。阻断b2 GPI与这些蛋白质或细胞表面受体的相互作用可以减轻aPL的病理作用。为了设计抑制剂，重要的是要知道复合物中结合界面的结构细节。没有任何b2 GPI复合物的结构信息。X射线晶体学用于确定b2 GPI复合物与凝血酶、纤溶酶原和ApoER 2的结合界面处的结构。复合物形成的肽抑制剂将根据蛋白质复合物中接触表面的结构信息进行设计和优化。肽抑制剂可以为开发用于潜在药理学应用的非肽b2 GPI拮抗剂提供起点，并且可以用作研究b2 GPI在止血中的生理作用及其在APS中的病理作用的研究工具。