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首页> 外文期刊>Journal of cellular biochemistry. >Dynamic perspectives into the mechanisms of mutation‐induced p53‐DNA binding loss and inactivation using active perturbation theory: Structural and molecular insights toward the design of potent reactivators in cancer therapy
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Dynamic perspectives into the mechanisms of mutation‐induced p53‐DNA binding loss and inactivation using active perturbation theory: Structural and molecular insights toward the design of potent reactivators in cancer therapy

机译：动态视角进入突变诱导的P53-DNA结合损失和使用积极扰动理论的灭活机制：对癌症治疗中有效反应器设计的结构和分子见解

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Abstract The DNA‐binding ability of p53 represents the crux of its tumor suppressive activities, which involves transcriptional activation of target genes responsible for apoptosis and cell‐cycle arrest. Mutational occurrences within or in close proximity to the DNA‐binding surface of p53 have accounted for the loss of direct DNA‐binding ability and inactivation implicated in many cases of cancer. Moreover, the design of therapeutic compounds that can restore DNA‐binding ability in p53 mutants has been identified as a way forward in curtailing their oncogenic activities. However, there is still the need for more insights into evaluate the perturbations that occur at the DNA‐binding interface of mp53 relative to DNA‐binding loss, inactivation, and design of potent reactivators, hence the purpose of this study. Therefore, we evaluated p53‐structural (R175H) and contact (R273C) mutational effects using tunnel perturbation analysis and other computational tools. We identified significant perturbations in the active tunnels of p53, which resulted in altered geometry and loss, unlike in the wild‐type p53. This corroborated with structural, DNA‐binding, and interaction network analysis, which showed that loss of flexibility, repulsion of DNA‐interactive residues, and instability occurred at the binding interface of both mutants. Also, these mutations altered bonding interactions and network topology at the DNA‐binding interface, resulting in the reduction of p53‐DNA binding proximity and affinity. Therefore, these findings would aid the structure‐based design of novel chemical entities capable of restoring p53‐DNA binding and activation.
机译：摘要P53的DNA结合能力代表其肿瘤抑制活性的关键，涉及负责细胞凋亡和细胞循环骤停的靶基因的转录激活。在p53的DNA结合表面内或紧邻或紧邻P53的突变事件占导致DNA结合能力的丧失，并且在许多癌症情况下涉及灭活。此外，可以鉴定在P53突变体中恢复DNA结合能力的治疗化合物的设计已被鉴定为缩减其致癌活性的前进方向。然而，仍然需要更多的见解，评估MP53的DNA结合界面相对于DNA结合损失，灭活和设计有效反应器的设计发生的扰动，因此该研究的目的。因此，我们使用隧道扰动分析和其他计算工具评估P53-结构（R175H）和接触（R273C）突变效应。我们在P53的主动隧道中识别出显着的扰动，这导致几何形状和损失改变，与野生型P53不同。这与结构，DNA结合和相互作用网络分析相关，表明，在两个突变体的结合界面处发生柔韧性，排斥力的丧失，抑制性，并且发生不稳定性。此外，这些突变在DNA结合界面处改变了键合相互作用和网络拓扑，导致降低p53-DNA结合接近和亲和力。因此，这些发现将有助于能够恢复P53-DNA结合和活化的新化学实体的基于结构的设计。

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