K I VARUGHESE PRT TIME

这个子项目是许多利用 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。 血管性血友病因子A型结构域的一个或多个拷贝的存在鉴定了通常参与由特定分子相互作用控制的生物学过程的蛋白质超家族，其性质通常是粘附性的。我们已经解决了原型的血管性血友病因子A1结构域的晶体结构，血小板的抗出血活性所必需的，在复杂的功能阻断抗体，NMC-4，在2.2 º分辨率。这导致了对血小板受体（糖蛋白Iba）的推定结合沟的识别，该结合沟由两个相邻的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，这表明了一种假设的调节蛋白质组装和异源配体结合的机制，该机制由A型结构域的嗜同性相互作用介导。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的结构将是本提案的重点。

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.