R Hephzibah Cathryn, C George Priya Doss
Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, India.
J Biomol Struct Dyn. 2025 Feb;43(2):798-812. doi: 10.1080/07391102.2023.2283793. Epub 2023 Nov 21.
The P53 protein, a cancer-associated transcriptional factor and tumor suppressor, houses a Zn ion in its DNA-binding domain (DBD), essential for sequence-specific DNA binding. However, common mutations at position 273, specifically from Arginine to Histidine and Cysteine, lead to a loss of function as a tumor suppressor, also called DNA contact mutations. The mutant (MT) P53 structure cannot stabilize DNA due to inadequate interaction. To investigate the conformational changes, we performed a comparative molecular dynamic simulation (MDS) to study the effect of the P53-Wildtype (P53-WT) and the DNA contact mutations (R273H and R273C) on the DBD. Our research indicated that the DNA binding bases lose Hydrogen bonds (H bonds) when mutated to P53-R273H and P53-R273C during the simulation. We employed tools, such as PDIviz to highlight the contacts with DNA bases and backbone, major and minor grooves, and various pharmacophore forms of atoms. The contact maps for R273H and R273C were generated using the COZOID tool, which displayed changes in the frequency of the amino acids and DNA bases interaction in the DNA binding domain. These residues have diminished interactions, and the zinc-binding domain shows significant movements by Zn ion binding to the phosphate group of the DNA, moving away from its binding sites. In conclusion, our research suggests that R273H and R273C each have unique stability and self-assembly properties. This understanding might assist researchers in better comprehending the function of the p53 protein and its importance in cancer.Communicated by Ramaswamy H. Sarma.
P53蛋白是一种与癌症相关的转录因子和肿瘤抑制因子，其DNA结合结构域（DBD）中含有一个锌离子，这对于序列特异性DNA结合至关重要。然而，273位的常见突变，特别是从精氨酸突变为组氨酸和半胱氨酸，会导致作为肿瘤抑制因子的功能丧失，也称为DNA接触突变。由于相互作用不足，突变型（MT）P53结构无法稳定DNA。为了研究构象变化，我们进行了比较分子动力学模拟（MDS），以研究P53野生型（P53-WT）和DNA接触突变（R273H和R273C）对DBD的影响。我们的研究表明，在模拟过程中，当突变为P53-R273H和P53-R273C时，DNA结合碱基失去了氢键（H键）。我们使用了诸如PDIViz等工具来突出与DNA碱基和骨架、大沟和小沟以及各种原子药效团形式的接触。使用COZOID工具生成了R273H和R273C的接触图，该图显示了DNA结合结构域中氨基酸与DNA碱基相互作用频率的变化。这些残基的相互作用减弱，锌结合结构域显示出锌离子与DNA磷酸基团结合并从其结合位点移开的显著移动。总之，我们的研究表明R273H和R273C各自具有独特的稳定性和自组装特性。这种理解可能有助于研究人员更好地理解p53蛋白的功能及其在癌症中的重要性。由拉马斯瓦米·H·萨尔马传达。
