Mimicry of Amyloid Oligomers

项目摘要/摘要：淀粉样蛋白低聚物的模拟 淀粉样蛋白低聚物现在被认为是阿尔茨海默氏症、帕金森氏症 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，并很可能开发药物来预防或治疗这些疾病。 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 异质性和动态性，形成各种尺寸和结构，可以相互转换。述低聚物 亚稳的，其中原纤维是更稳定的物质。只有少数研究提供了 淀粉样蛋白低聚物的原子分辨率。到目前为止，还没有原子分辨率的结构， β-淀粉样肽的寡聚体，Abeta，40或42个氨基酸的多肽，与 老年痴呆症 该提案旨在通过结合关键的结构来确定Abeta形成的低聚物的结构。 将Abeta片段转化为大环β折叠肽，设计用于模拟关键的β-发夹结构 被认为构成Abeta寡聚体的嵌段。PI已经确定了X射线晶体结构 在三聚体的原子分辨率下，形成的大环β-折叠肽含有来自中心的片段， 和Abeta的C末端区域。三聚体具有迄今为止前所未有的结构， 在三个顶点处挤在一起的β-发夹的三角形排列。三聚体进一步组装成 形成六聚体和十二聚体。 这项建议旨在建立在这些三聚体和更高阶的低聚组装的发现。的 一个广泛的总体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学性质。为了实现这些目标，PI将 大环β折叠肽，包括不同方面的Abeta结构，确定X射线 这些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 细胞毒性的机制，并将它们的细胞毒性与它们的晶体结构相关联， 生物物理学研究其溶液相性质。

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.