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dc.creatorLeontiadou, Hari
dc.creatorGaldadas, Ioannis
dc.creatorCournia, Zoe
dc.date2017-04-27
dc.date.accessioned2017-05-06T13:20:57Z
dc.date.available2017-05-06T13:20:57Z
dc.identifier.urihttp://hdl.handle.net/21.15102/VISEEM-254
dc.descriptionThis dataset contains Molecular Dynamics simulations trajectories of the full length Wild-Type (normal) PI3Ka. These simulations are provided in two independent replicate trajectories (Run 1 and Replicate 1)
dc.description.abstractThe kinase PI3Ka is involved in fundamental cellular processes such as cell proliferation and differentiation and is frequently mutated in human malignancies. One of the most common mutations is E545K, which results in an amino acid change of opposite charge. It has been recently proposed that in this oncogenic charge-reversal mutation, the interactions between the protein catalytic and regulatory subunits are abrogated, resulting in loss of regulation and constitutive PI3Ka activity, which can lead to oncogenesis. To assess the mechanism of protein overactivation, extensive MD simulations were performed to examine conformational changes differing among wild type (WT) and mutant proteins as they occur in the microsecond timescale. In the mutant protein form, we observe a spontaneous detachment of the nSH2 PI3Ka domain (regulatory subunit, p85a) from the helical domain (catalytic subunit, p110a), which results in significant loss of communication between the regulatory and catalytic subunits. We examine the allosteric network of the two proteins and show that a cluster of residues around the mutation is key in delivering communication signals between the catalytic and regulatory subunits. Our results demonstrate the dynamical and structural differences of the two proteins in atomic detail and indicate a possible mechanism for the enzyme overactivation.
dc.description.sponsorshipVI-SEEM
dc.publisherBRFAA
dc.subjectcancer, PI3Ka, PI3K alpha, Molecular Dynamics simulations, mutation, E545K, oncogene, breast cancer
dc.titleInsights into the mechanism of the PIK3CA E545K activating mutation using MD simulations
dc.rights.licenseFree upon contacting the authors


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