CRYSTAL STRUCTURE OF VON WILLEBRAND FACTOR A1 DOMAIN

存在一个或多个冯维勒布兰德因子A型拷贝 结构域识别蛋白质的超家族，通常涉及 由特定分子相互作用控制的生物过程， 通常具有粘性。 我们已经解决了晶体结构的 原型von Willebrand因子A1结构域，对于 血小板的抗出血活性， 阻断抗体，NMC-4，2.2 E分辨率。 这导致 识别血小板受体的假定结合沟， 糖蛋白Iba，由两个相邻的？螺旋和_链。 该结构还显示A1结构域对之间的接触界面， 提出了一种假设的调节蛋白质的机制， 组装和异源配体结合介导的 A型结构域的相互作用。 A1结构域与 糖蛋白Iba是止血所必需的。 某些突变 在A1结构域上消除出血。 某些其他突变会增加 结合的亲和力。 研究这些突变体的结构， 调节剂Botrocetin的结构将是本文的重点 提议

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.