Young Lydia M, Ashcroft Alison E, Radford Sheena E
Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
Curr Opin Chem Biol. 2017 Aug;39:90-99. doi: 10.1016/j.cbpa.2017.06.008. Epub 2017 Jun 22.
Understanding the mechanisms of amyloid formation and toxicity remain major challenges. Although substantial progress has been made in the development of methods able to identify the species formed during self-assembly and to describe the kinetic mechanisms of aggregation, the structure(s) of non-native species, including potentially toxic oligomers, remain elusive. Moreover, how fibrils contribute to disease remains unclear. Here we review recent advances in the development of small molecules and other reagents that are helping to define the mechanisms of protein aggregation in molecular detail. Such probes form a powerful platform with which to better define the mechanisms of structural conversion into amyloid fibrils and may provide the much-needed stepping stone for future development of successful therapeutic agents.
了解淀粉样蛋白形成和毒性的机制仍然是重大挑战。尽管在开发能够识别自组装过程中形成的物种并描述聚集动力学机制的方法方面已经取得了实质性进展，但非天然物种的结构，包括潜在有毒的寡聚体，仍然难以捉摸。此外，原纤维如何导致疾病仍不清楚。在这里，我们回顾了小分子和其他试剂开发方面的最新进展，这些进展有助于在分子细节上定义蛋白质聚集的机制。此类探针形成了一个强大的平台，可借此更好地定义向淀粉样原纤维结构转化的机制，并可能为未来成功治疗药物的开发提供急需的垫脚石。
