CRYSTAL STRUCTURE OF VON WILLEBRAND FACTOR A1 DOMAIN

血管性血友病因子 A1 结构域的晶体结构

• 批准号: 6119419
• 负责人: KOTTAYIL I VARUGHESE
• 金额: --
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2000-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6119419
• 关键词: biomaterials; hematology; proteins

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.

存在一个或多个 A 型血管性血友病因子副本 结构域识别通常涉及的蛋白质超家族 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 原型冯维勒布兰德因子 A1 结构域，对于 血小板的抗出血活性，与功能复杂 封闭抗体 NMC-4，分辨率为 2.2 E。 这导致了 识别血小板受体的假定结合槽， 糖蛋白Iba，由两个相邻的α-螺旋和一条_-链形成。 该结构还显示了 A1 域对之间的接触界面， 提出了蛋白质调节的假设机制 由同源介导的组装和异源配体结合 A 型域的相互作用。 A1 结构域与 糖蛋白 Iba 对于止血至关重要。 某些突变 对A1域取消出血。 某些其他突变增加 结合的亲和力。 研究这些突变体的结构 调节剂 Botrocetin 的结构将是本次研究的重点 提议。