CRYSTAL STRUCTURE OF VON WILLEBRAND FACTOR A1 DOMAIN

存在一个或多个von Willebrand因子A型副本 结构域识别一个蛋白质超家族，通常参与 由特定分子相互作用控制的生物过程， 在性质上通常是粘性的。我们已经解决了它的晶体结构 典型的von Willebrand因子A1结构域，对于 血小板的抗出血活性，与功能的复合体 封闭抗体NMC-4，分辨率为2.2E。这导致了 识别可能的血小板受体结合槽， 糖蛋白Iba，由两个相邻的α-螺旋和α-链组成。 该结构还显示了A1结构域对之间的接触界面， 提出了一种假想的蛋白质调节机制 高亲性分子介导的组装和异源配体结合 A型结构域的相互作用。A1结构域与 糖蛋白Iba对于止血是必不可少的。某些突变 在A1区域消除出血。某些其他突变增加 捆绑的亲和力。研究这些突变体的结构和 调节剂Botrocetin的结构将是本次研究的重点 求婚。

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 E resolution. This has led to the recognition of a putative binding groove for the platelet receptor, glycoprotein Iba, formed by two adjacent ?-helices and a _-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.