Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, 92093, USA.
Dana Farber Cancer Institute, Center for Protein Degradation, Boston, MA, 02215, USA.
Curr Opin Struct Biol. 2021 Apr;67:187-194. doi: 10.1016/j.sbi.2020.11.005. Epub 2021 Jan 2.
The tumor suppressor p53 plays a vital role in responding to cell stressors such as DNA damage, hypoxia, and tumor formation by inducing cell-cycle arrest, senescence, or apoptosis. Expression level alterations and mutational frequency implicates p53 in most human cancers. In this review, we show how both computational and experimental methods have been used to provide an integrated view of p53 dynamics, function, and reactivation potential. We argue that p53 serves as an exceptional case study for developing methods in modeling intrinsically disordered proteins. We describe how these methods can be leveraged to improve p53 reactivation molecule design and other novel therapeutic modalities, such as PROteolysis TARgeting Chimeras (PROTACs).
肿瘤抑制因子 p53 在应对细胞应激方面发挥着至关重要的作用，如 DNA 损伤、缺氧和肿瘤形成，通过诱导细胞周期停滞、衰老或细胞凋亡来实现。p53 的表达水平改变和突变频率暗示其与大多数人类癌症有关。在这篇综述中，我们展示了计算和实验方法如何被用于提供对 p53 动力学、功能和重新激活潜力的综合视图。我们认为，p53 是开发用于模拟固有无序蛋白的方法的一个极好的案例研究。我们描述了如何利用这些方法来改善 p53 重新激活分子的设计和其他新型治疗方式，如 PROteolysis TARgeting Chimeras (PROTACs)。
