Mimicry of Amyloid Oligomers

淀粉样蛋白寡聚物的模拟

• 批准号: 9205515
• 负责人: JAMES S NOWICK
• 金额: $ 29.14万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9205515
• 关键词: Alzheimer' s Disease; Amino Acids; Amyloid; Amyloid beta-Protein; Amyloidosis; Biological; Biological Models; C-terminal; Chemical Models; Disease; Goals; Knowledge; Lead; Measures; Molecular; Mutation; Neurodegenerative Disorders; Parkinson Disease; Peptides; Pharmaceutical Preparations; Phase; Prion Diseases; Property; Proteins; Resolution; Roentgen Rays; Structure; Tail; Thermodynamics; abeta oligomer; amyloid peptide; beta pleated sheet; biophysical analysis; biophysical properties; crosslink; cytotoxicity; design; mimicry; novel therapeutics; polypeptide; prevent

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.

项目摘要/摘要：淀粉样蛋白低聚物的模仿 淀粉样蛋白低聚物现在被认为是阿尔茨海默氏病的破坏分子物种，帕金森氏症 疾病和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，并且很可能开发药物以预防或治疗这些药物 疾病。在高分辨率上研究低分辨率的结构是具有挑战性的，因为低聚物是 异质和动态，形成可以互连的各种尺寸和结构。低聚物是 可稳态，纤维是热力学稳定的物种。只提供了少数研究 淀粉样蛋白低聚物在原子分辨率上的一瞥。到目前为止，没有原子分辨率结构 β-淀粉样蛋白肽的低聚物Abeta，40或42个氨基酸多肽与与 阿尔茨海默氏病。 该建议旨在通过合并钥匙来确定Abeta形成的低聚物的结构 Abeta的碎片成巨型β-β-β-型肽，旨在模仿关键的β发hairpin建筑 被认为构成Abeta低聚物的块。 PI已确定X射线晶体结构 在原子分辨率上，三聚体形成的大环β-β- 和Abeta的C末端区域。三聚体迄今为止的空前结构，由 β发pins的三角形布置在三个顶点包装在一起。三聚机进一步组装到 形成六聚体和企业。 该建议旨在建立在这些三聚体和高阶寡聚组件的基础上。这 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特性。为了实现这些目标，PI将合成 大环β-β-β-型肽，结合了Abeta结构的不同方面，确定X射线 这些肽形成的低聚物的晶体学结构，测量其细胞毒性，阐明它们 细胞毒素的机制，并通过其细胞毒性及其晶体学结构相关联 其溶液相特性的生物物理研究。