Mimicry of Amyloid Oligomers

项目摘要/摘要：淀粉样低聚物的仿制 淀粉样寡聚体现在被认为是阿尔茨海默病和帕金森病的破坏性分子物种 疾病，以及许多其他淀粉样蛋白疾病。了解这些低聚物的结构对于 了解它们的作用机制，并很有可能开发预防或治疗这些疾病的药物 疾病。在高分辨率下研究低聚物的结构是具有挑战性的，因为低聚物是 异质和动态，形成了各种大小和结构，可以相互转换。低聚物是 亚稳态，纤维是热力学上更稳定的物种。只有几项研究提供了 原子分辨率的淀粉样寡聚体的一瞥。到目前为止，还没有原子分辨结构 β-淀粉样多肽的寡聚体，Abeta，40或42个氨基酸的多肽与 阿尔茨海默氏症。 这项提议旨在通过掺入Key来确定Abeta形成的低聚物的结构 Abeta片段为大环β-折叠多肽，旨在模拟关键的β-发夹构建 被认为是组成Abeta低聚物的嵌段。等电点测定了X射线晶体结构 在原子分辨率下，三聚体形成的大环β-片肽含有来自中央的片段 和Abeta的C-末端区域。三聚体具有前所未有的结构，由一个 在三个顶点处聚集在一起的贝塔发夹的三角形排列。三聚体进一步组装成 形成六角体和十二角体。 这项提议旨在建立在这些三聚体和更高阶低聚组件发现的基础上。这个 广泛的首要目标是了解原子分辨率结构之间的关系 低聚物及其生物学和生物物理性质。为了实现这些目标，PI将综合 包含不同方面的Abeta结构的大环β-片肽，决定了X射线 这些多肽形成的低聚物的晶体结构，测量它们的细胞毒性，阐明它们的 它们的细胞毒性机制，并通过电子显微镜观察它们的晶体结构 对其溶液相性质的生物物理研究。

Project Summary/Abstract: Mimicry of Amyloid Oligomers Amyloid oligomers now thought to be the damaging molecular species in Alzheimer's disease, Parkinson's disease, and many other amyloid diseases. Understanding the structures of these oligomers is essential to understanding their mechanism of action, and quite possibly to developing drugs to prevent or treat these diseases. Studying the structures of the oligomers at high resolution is challenging, because the oligomers are heterogeneous and dynamic, forming a variety of sizes and structures that can interconvert. The oligomers are metastable, with fibrils being the more thermodynamically stable species. Only a few studies have provided glimpses of amyloid oligomers at atomic resolution. Thus far, the there are no atomic-resolution structures of oligomers of the beta-amyloid peptide, Abeta, the 40 or 42 amino acid polypeptide closely associated with Alzheimer's disease. This proposal aims to determine the structures of oligomers formed by Abeta by incorporating key fragments of Abeta into macrocyclic beta-sheet peptides designed to mimic the key beta-hairpin building blocks that are thought to make up Abeta oligomers. The PI has determined X-ray crystallographic structures at atomic resolution of trimers formed macrocyclic beta-sheet peptides containing fragments from the central and the C-terminal regions of Abeta. The trimers have a hitherto unprecedented structure consisting of a triangular arrangement of beta-hairpins that pack together at the three vertices. The trimers further assemble to form hexamers and dodecamers. This proposal aims to build on the discovery of these trimers and higher-order oligomeric assemblies. The broad overarching goal is to understand the relationship between the atomic-resolution structures of the oligomers and their biological and biophysical properties. To achieve these goals, the PI will synthesize macrocyclic beta-sheet peptides that incorporate different aspects of Abeta structure, determine the X-ray crystallographic structures of the oligomers that these peptides form, measure their cytotoxicity, elucidate their mechanisms of cytotoxcity, and correlate their cytotoxicity and their crystallographic structure by means of biophysical studies of their solution-phase properties.