Small-molecule stabilization of the p53-14-3-3 protein-protein interaction
Small-molecule stabilization of the p53-14-3-3 protein-protein interaction
复制标题
DOI：
10.1002/1873-3468.12723
复制
发表时间：
2017-08-01
期刊：
影响因子：
3.5
通讯作者：
Ottmann, Christian
中科院分区：
文献类型：
--
作者：
Doveston, Richard G.;Kuusk, Ave;Ottmann, Christian
14-3-3蛋白是肿瘤抑制因子p53的正调控因子，其突变与许多人类癌症有关。目前针对p53的策略包括恢复野生型功能或抑制与其关键负调节因子MDM 2的相互作用。尽管这些策略的功效，稳定p53与正调控因子的相互作用并因此增强肿瘤抑制活性的替代方法尚未被探索。在这里，我们报告的第一个例子的小分子稳定的14-3-3 - p53蛋白质-蛋白质相互作用（PPI），并证明这种方法作为一种治疗方式的潜力。我们还观察到，在存在稳定分子的情况下，生物物理学和晶体学数据之间存在脱节，这在14-3-3 PPI中是不寻常的。
14-3-3 proteins are positive regulators of the tumor suppressor p53, the mutation of which is implicated in many human cancers. Current strategies for targeting of p53 involve restoration of wild-type function or inhibition of the interaction with MDM2, its key negative regulator. Despite the efficacy of these strategies, the alternate approach of stabilizing the interaction of p53 with positive regulators and, thus, enhancing tumor suppressor activity, has not been explored. Here, we report the first example of small-molecule stabilization of the 14-3-3 - p53 protein-protein interaction (PPI) and demonstrate the potential of this approach as a therapeutic modality. We also observed a disconnect between biophysical and crystallographic data in the presence of a stabilizing molecule, which is unusual in 14-3-3 PPIs.