K I VARUGHESE PRT TIME

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。血管性血友病因子A型结构域的一个或多个拷贝的存在确定了一个超家族的蛋白质，通常参与由特定分子相互作用控制的生物过程，通常在性质上是粘附的。我们已经解决了原型血管性血液病因子A1结构域的晶体结构，它对血小板的抗出血活性至关重要，与功能阻断抗体NMC-4复合物，在2.2¿¿分辨率下。这导致了血小板受体（糖蛋白Iba）的推定结合槽的识别，该结合槽由两个相邻的α -螺旋和β -链组成。该结构还显示了A1结构域对之间的接触界面，这表明a型结构域的亲同性相互作用介导了蛋白质组装和异源配体结合的调节机制。A1结构域与糖蛋白Iba的结合对止血至关重要。A1结构域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乳素调节剂的结构将是本研究的重点。

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.