Molecular Modeling and Drug Design Laboratory, Pharmacology Research Division, Bangladesh Council of Scientific and Industrial Research, Chittagong, 4220, Bangladesh.
Molecular Modeling and Drug Design Laboratory, Pharmacology Research Division, Bangladesh Council of Scientific and Industrial Research, Chittagong, 4220, Bangladesh; Department of Biochemistry and Biotechnology, University of Science & Technology Chittagong, Chittagong, 4202, Bangladesh.
Comput Biol Chem. 2019 Apr;79:127-136. doi: 10.1016/j.compbiolchem.2019.02.003. Epub 2019 Feb 15.
In SCF (Skp, Cullin, F-box) ubiquitin-protein ligase complexes, S-phase kinase 2 (SKP2) is one of the major players of F-box family, that is responsible for the degradation of several important cell regulators and tumor suppressor proteins. Despite of having significant evidence for the role of SKP2 on tumorgenesis, there is a lack of available data regarding the effect of non-synonymous polymorphisms. In this communication, the structural and functional consequences of non-synonymous single nucleotide polymorphisms (nsSNPs) of SKP2 have been reported by employing various computational approaches and molecular dynamics simulation. Initially, several computational tools like SIFT, PolyPhen-2, PredictSNP, I-Mutant 2.0 and ConSurf have been implicated in this study to explore the damaging SNPs. In total of 172 nsSNPs, 5 nsSNPs were identified as deleterious and 3 of them were predicted to be decreased the stability of protein. Guided from ConSurf analysis, P101L (rs761253702) and Y346C (rs755010517) were categorized as the highly conserved and functional disrupting mutations. Therefore, these mutations were subjected to three dimensional model building and molecular dynamics simulation study for the detailed structural consequences upon the mutations. The study revealed that P101L and Y346C mutations increased the flexibility and changed the structural dynamics. As both these mutations are located in the most functional regions of SKP2 protein, these computational insights might be helpful to consider these nsSNPs for wet-lab confirmatory analysis as well as in rationalizing future population based studies and structure based drug design against SKP2.
在 SCF（Skp、Cullin、F-box）泛素蛋白连接酶复合物中，S 期激酶 2（SKP2）是 F-box 家族的主要成员之一，负责降解几种重要的细胞调节剂和肿瘤抑制蛋白。尽管有大量证据表明 SKP2 在肿瘤发生中的作用，但关于非同义核苷酸多态性的影响的数据却很少。在本通讯中，通过采用多种计算方法和分子动力学模拟，报道了 SKP2 非同义单核苷酸多态性（nsSNP）的结构和功能后果。最初，本研究中使用了多种计算工具，如 SIFT、PolyPhen-2、PredictSNP、I-Mutant 2.0 和 ConSurf，以探索有害 SNPs。在总共 172 个 nsSNP 中，有 5 个被鉴定为有害，其中 3 个被预测降低了蛋白质的稳定性。根据 ConSurf 分析，P101L（rs761253702）和 Y346C（rs755010517）被归类为高度保守和功能破坏突变。因此，这些突变被用于三维模型构建和分子动力学模拟研究，以详细研究突变对结构的影响。研究表明，P101L 和 Y346C 突变增加了蛋白质的灵活性并改变了其结构动力学。由于这两个突变都位于 SKP2 蛋白的最功能区域，这些计算结果可能有助于考虑这些 nsSNP 进行湿实验室验证分析，以及在未来基于人群的研究和基于结构的 SKP2 药物设计中合理化这些突变。
