Department of Genetic Engineering and Biotechnology, School of Life Sciences, Shahjalal University of Science and Technology, Sylhet, Bangladesh.
PLoS One. 2021 Nov 4;16(11):e0259691. doi: 10.1371/journal.pone.0259691. eCollection 2021.
Cycline-dependent kinase 4 (CDK4), an enzyme of the cycline dependent or Ser/Thr protein kinase family, plays a role in cell cycle progression (G1 phase) by phosphorylating a tumor suppressor protein called pRB. Alteration of this enzyme due to missense mutation/ nonsynonymous single nucleotide polymorphisms (nsSNPs) are responsible for various types of cancer progression, e.g. melanoma, lung cancer, and breast cancer. Hence, this study is designed to identify the malignant missense mutation of CDK4 from the single nucleotide polymorphism database (dbSNP) by incorporating computational algorithms. Out of 239 nsSNPs; G15S, D140Y and D140H were predicted to be highly malignant variants which may have a devastating impact on protein structure or function. We also found defective binding motif of these three mutants with the CDK4 inhibitor ribociclib and ATP. However, by incorporating molecular dynamic simulation, our study concludes that the superiority of G15S than the other two mutants (D140Y and D140H) in destabilizing proteins nature.
周期蛋白依赖性激酶 4（CDK4）是细胞周期蛋白依赖性或丝氨酸/苏氨酸蛋白激酶家族的一种酶，通过磷酸化一种称为 pRB 的肿瘤抑制蛋白在细胞周期进展（G1 期）中发挥作用。由于错义突变/非同义单核苷酸多态性（nsSNP）导致这种酶的改变是各种类型癌症进展的原因，例如黑色素瘤、肺癌和乳腺癌。因此，本研究旨在通过整合计算算法，从单核苷酸多态性数据库（dbSNP）中鉴定 CDK4 的恶性错义突变。在 239 个 nsSNP 中；G15S、D140Y 和 D140H 被预测为高度恶性变异体，可能对蛋白质结构或功能产生破坏性影响。我们还发现这三个突变体与 CDK4 抑制剂瑞博西利和 ATP 的结合基序有缺陷。然而，通过整合分子动力学模拟，我们的研究得出结论，G15S 比其他两个突变体（D140Y 和 D140H）在破坏蛋白质本质的稳定性方面具有优势。
