Omar Sara Ibrahim, Tuszynski Jack
Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Department of Physics, Faculty of Science, University of Alberta, Edmonton, Alberta, Canada.
Oncotarget. 2018 Dec 14;9(98):37137-37156. doi: 10.18632/oncotarget.26440.
One of the most important tumor suppressor proteins in eukaryotic cells is the transcription factor called p53. The importance of this protein in cells comes from the fact that it regulates a wide variety of cellular processes including the cell cycle, metabolism, DNA repair, senescence and apoptosis. In cancer cells, p53 is a major target as the most mutated protein, which has led to the search for potential activators of the mutant protein. Currently, the only mutated-p53 activator in clinical trials is a small molecule called APR-246. There is evidence that the active metabolite of APR-246 binds covalently to mutant p53 and restores its wild-type (wt) activity. In this work, we created atomistic models of the wt, mutant and drugged mutant p53 proteins each in complex with DNA. Using molecular dynamics simulations we generated equilibrated models of the complexes. Detailed analysis revealed that the binding of the APR-246 active metabolite to the mutant proteins alters their interaction with DNA. In particular, the binding of the molecule at loop L1 of the protein allows the loop to anchor the protein to DNA similarly to wt p53. Several important p53-DNA interactions lost due to mutation were also restored in the drugged mutants. These findings, not only provide a possible mechanism of action of this drug, but also criteria to use in virtual screening campaigns for other p53 activators.
真核细胞中最重要的肿瘤抑制蛋白之一是一种名为p53的转录因子。该蛋白在细胞中的重要性源于它能调节多种细胞过程，包括细胞周期、代谢、DNA修复、衰老和凋亡。在癌细胞中，p53是最易发生突变的蛋白，也是主要靶点，这促使人们寻找突变蛋白的潜在激活剂。目前，临床试验中唯一的突变型p53激活剂是一种名为APR - 246的小分子。有证据表明，APR - 246的活性代谢产物与突变型p53共价结合并恢复其野生型（wt）活性。在这项研究中，我们构建了野生型、突变型和药物处理后的突变型p53蛋白与DNA复合物的原子模型。通过分子动力学模拟，我们生成了复合物的平衡模型。详细分析表明，APR - 246活性代谢产物与突变蛋白的结合改变了它们与DNA的相互作用。特别是，该分子与蛋白环L1的结合使环能够像野生型p53一样将蛋白锚定到DNA上。药物处理后的突变体中，一些因突变而丧失的重要p53 - DNA相互作用也得以恢复。这些发现不仅为这种药物提供了一种可能的作用机制，也为其他p53激活剂的虚拟筛选活动提供了标准。
