Investigating the Structure and Dynamics of the PIK3CA Wild-Type and H1047R Oncogenic Mutant

• DOI: 10.1371/journal.pcbi.1003895
• Publication Date: 2014-10-23T20:55:39Z
• Authors: Paraskevi Gkeka; Thomas Evangelidis; Maria Pavlaki; Vasiliki Lazani; Savvas Christofor...; Bogos Agianian; Zoe Cournia
• Keywords: P110α; Mutant protein; Wild type

The PIK3CA gene is one of the most frequently mutated oncogenes in human cancers. It encodes p110α, catalytic subunit phosphatidylinositol 3-kinase alpha (PI3Kα), which activates signaling cascades leading to cell proliferation, survival, and growth. frequent mutation H1047R, results enzymatic overactivation. Understanding how H1047R causes enhanced activity protein atomic detail central developing mutant-specific therapeutics for cancer. To this end, Surface Plasmon Resonance (SPR) experiments Molecular Dynamics (MD) simulations were carried out both wild-type (WT) mutant proteins. An expanded positive charge distribution on membrane binding regions with respect WT observed through MD simulations, justifies increased ability variant bind membranes rich anionic lipids our SPR experiments. Our further support an auto-inhibitory role C-terminal tail protein, abolished due loss crucial intermolecular interactions. Moreover, Functional Mode Analysis reveals that alters twisting motion N-lobe kinase domain C-lobe shifts position conserved P-loop residues vicinity active site. These findings demonstrate dynamical structural differences two proteins propose a mechanism overactivation protein. may be utilized design PI3Kα inhibitors exploit altered conformation.