B2GPI COMPLEXES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本研究的目的是为开发有效和安全的β2-糖蛋白I(B2GPI)依赖的抗磷脂综合征(APS)的治疗方法奠定结构基础。APS与复发性血栓形成有关。APS的病理机制很复杂，但很明显，针对结合阴离子磷脂的蛋白的自身免疫抗磷脂抗体(APL)在该病中起着重要作用。B2GPI是APL的主要目标。B2GPI在被自身免疫抗体二聚化后获得病理特性，从而增加其局部浓度，促进与其他蛋白质和细胞膜的相互作用。阻断b2GPI与这些蛋白或细胞表面受体的相互作用可能会减轻APL的病理效应。要设计一种抑制剂，重要的是要知道复合体中结合界面的结构细节。目前还没有关于任何b2GPI络合物的结构信息。X射线结晶学用于确定b2GPI与凝血酶、纤溶酶原和ApoER2结合界面的结构。将根据蛋白质复合体中接触面的结构信息来设计和优化形成复合体的多肽抑制剂。这些多肽抑制剂可能为开发具有潜在药理应用的非肽b2GPI拮抗剂提供起点，并可作为研究b2GPI在止血中的生理作用及其在APS中的病理作用的研究工具。

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.