title: Cancer associated E17K mutation causes rapid conformational drift in AKT1 pleckstrin homology (PH) domain.
abstract: BACKGROUND
  AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is one of the most frequently activated proliferated and survival pathway of cancer. Recently it has been shown that E17K mutation in the Pleckstrin Homology (PH) domain of AKT1 protein leads to cancer by amplifying the phosphorylation and membrane localization of protein. The mutant has shown resistance to AKT1/2 inhibitor VIII drug molecule. In this study we have demonstrated the detailed structural and molecular consequences associated with the activity regulation of mutant protein.
  
  
  METHODS
  The docking score exhibited significant loss in the interaction affinity to AKT1/2 inhibitor VIII drug molecule. Furthermore, the molecular dynamics simulation studies presented an evidence of rapid conformational drift observed in mutant structure.
  
  
  RESULTS
  There was no stability loss in mutant as compared to native structure and the major cation-π interactions were also shown to be retained. Moreover, the active residues involved in membrane localization of protein exhibited significant rise in NHbonds formation in mutant. The rise in NHbond formation in active residues accounts for the 4-fold increase in the membrane localization potential of protein.
  
  
  CONCLUSIONS
  The overall result suggested that, although the mutation did not induce any stability loss in structure, the associated pathological consequences might have occurred due to the rapid conformational drifts observed in the mutant AKT1 PH domain.
  
  
  CONCLUSIONS
  The methodology implemented and the results obtained in this work will facilitate in determining the core molecular mechanisms of cancer-associated mutations and in designing their potential drug inhibitors.
authors.affiliation: Bioinformatics Division, School of Bio Sciences and Technology, Vellore Institute of Technology University, Vellore, Tamil Nadu, India.
authors.forename: Ambuj
authors.initials: A
authors.lastname: Kumar
authors.forename: Rituraj
authors.initials: R
authors.lastname: Purohit
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry*; D030562:Databases, Protein; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry* / Q000235:genetics; D011810:Quinoxalines / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: C532657:1,3-dihydro-1-(1-((4-(6-phenyl-1H-imidazo(4,5-g)quinoxalin-7-yl)phenyl)methyl)-4-piperidinyl)-2H-benzimidazol-2-one; D001562:Benzimidazoles; D011810:Quinoxalines; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt