K I VARUGHESE PRT TIME

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。 一个或多个von Willebrand因子A型结构域拷贝的存在识别了一个蛋白质超家族，通常参与由特定分子相互作用控制的生物过程，通常是粘附性的。我们已经解决了典型的von Willebrand因子A1结构域的晶体结构，这是血小板抗出血活性所必需的，与功能阻断抗体NMC-4的复合体，分辨率为2.2。这导致了对血小板受体糖蛋白Iba的假定结合槽的识别，该结合槽由两个相邻的α-螺旋和一个β-链形成。该结构还显示了A1结构域对之间的接触界面，这表明了一种假想的机制，即通过A型结构域的同亲相互作用调节蛋白质组装和异源配体结合。A1结构域与糖蛋白Iba的结合对于止血是必不可少的。A1结构域上的某些突变可以消除出血。某些其他突变增加了结合的亲和力。研究这些突变体的结构和调节剂Botrocetin的结构将是这一提议的重点。

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 presence of one or more copies of von Willebrand factor type A domain identifies a superfamily of proteins usually involved in biological processes controlled by specific molecular interactions, often adhesive in nature. We have solved the crystal structure of the prototypic von Willebrand factor A1 domain, essential for the antihemorrhagic activity of platelets, in complex with the function blocking antibody, NMC-4, at 2.2 ¿ resolution. This has led to the recognition of a putative binding groove for the platelet receptor, glycoprotein Iba, formed by two adjacent alpha-helices and a beta-strand. The structure also shows a contact interface between A1 domain pairs, suggesting a hypothetical mechanism for the regulation of protein assembly and heterologous ligand binding mediated by homophilic interactions of type A domains. The binding of the A1 domain to the glycoprotein Iba is essential to arrest bleeding. Certain mutations on the A1 domain abolish bleeding. Certain other mutations increase the affinity of binding. Studying the structures of these mutants and the structure of the modulator botrocetin will be the focus of this proposal.