title: Role of E542 and E545 missense mutations of PIK3CA in breast cancer: a comparative computational approach.
abstract: Recent statistics describe breast cancer as the leading cause of death among women across the world with varied causes and reasons. Lifestyle, diet, genetic and environmental factors introduce their generous contributions towards breast cancer, among which genetic factors have lately become one of the most important aspects in understanding the mechanism. Although various genes have already been reported in causing breast cancer, PIK3CA stands second on the list. Mutations observed in this gene have the ability to trigger the different activities of the cell, thereby bypassing the regular cellular cycle. Among the mutations in PIK3CA, three hotspot mutations were commonly reported, one in the catalytic domain (position HIS1047) and other two in the helical domain (position GLU542 and GLU545). In the helical domain of PIK3CA, the lysine substitution at 542-545 positions was significantly studied in causing breast cancer. To compare the deleterious effect of these mutations, in silico prediction tools along with molecular dynamics simulations and molecular docking approach was initiated to analyse the change in binding landscape upon mutation. In this comparative analysis, we report that the mere existence of mutant E545K can trigger the function of the protein but may not be as harmful as H1047R. Among the two mutations E542K and E545K, the latter shows the most deleterious effect that correlates with the previous reported experimental studies. We assume the results observed in this combinatorial computational study might further pave a better way for providing better treatment procedures.
authors: a Department of Integrative Biology, School of Biosciences and Technology , VIT University , Vellore , Tamil Nadu 632014 , India.
authors: D
authors: D
authors: Thirumal Kumar
authors: a Department of Integrative Biology, School of Biosciences and Technology , VIT University , Vellore , Tamil Nadu 632014 , India.
authors: C
authors: C
authors: George Priya Doss
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D047428:Protein Kinase Inhibitors; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D000077191:Wortmannin
keywords: E542K; E545K; PIK3CA; breast cancer; helical domain; molecular docking; molecular dynamics simulation; single nucleotide polymorphisms; wortmannin