ArticleScientific reports2018
Insights into the mechanism of the PIK3CA E545K activating mutation using MD simulations.
Article in Scientific reports, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 69 citations in OpenAlex.
- Integrated genomic and proteomic profiling reveals insights into chemoradiation resistance in cervical cancer.Molecular oncology · 2026Article
- A new functional assay reveals that membrane binding is critical for overactivation of the phosphoinositide 3-kinase H1047R mutant.The Journal of biological chemistry · 2026Article
- An interpretable molecular framework for predicting cancer driver missense mutations.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Oncogenic PI3Kα variants reveal graded conformational spectrum with mutation-specific cryptic pockets.Communications chemistry · 2026Article
- Understanding the conformational dynamics of PI3Kα due to helical domain mutations: insights from Markov state model analysis.Molecular diversity · 2025Article
- Oncogenic PI3Kα variants reveal graded conformational spectrum with mutation-specific cryptic pockets.bioRxiv : the preprint server for biology · 2025Article
- Structural and allosteric effects of the membrane-bound PI3Kα H1047R mutation and opportunities for drug discovery.Communications chemistry · 2025Article
- Review
- The Precision-Guided Use of PI3K Pathway Inhibitors for the Treatment of Solid Malignancies.Biomedicines · 2025Review
- Oncogenic activation ofGenes & diseases · 2025Review
- Clinical, genomic, and histopathologic diversity in cerebral cavernous malformations.Acta neuropathologica communications · 2025Article
- The multifaceted anticancer potential of luteolin: involvement of NF-κB, AMPK/mTOR, PI3K/Akt, MAPK, and Wnt/β-catenin pathways.Inflammopharmacology · 2025Review
- Mechanistic optimization of inavolisib combined with CDK4/6 inhibitors in the treatment of PIK3CA-mutated breast tumors.Frontiers in immunology · 2025Review
- Circulating tumor cells: indicators of cancer progression, plasticity and utility for therapies.Pathology oncology research : POR · 2025Review
- Free energy landscape of the PI3Kα C-terminal activation.Computational and structural biotechnology journal · 2024Article
- Ultrasensitive detection of circulating tumor DNA using a CRISPR/Cas9 nickase-driven 3D DNA walker based on a COF-AuNPs sensing platform.Mikrochimica acta · 2024Article
- Depicting Biomarkers for HER2-Inhibitor Resistance: Implication for Therapy in HER2-Positive Breast Cancer.Cancers · 2024Review
- Rare subclonal sequencing of breast cancers indicates putative metastatic driver mutations are predominately acquired after dissemination.Genome medicine · 2024Article
- The Study of PIK3CA Hotspot Mutations and Co-Occurring with EGFR, KRAS, and TP53 Mutations in Non-Small Cell Lung Cancer.OncoTargets and therapy · 2024Article
- Characterization of Lipid Alterations by OncogenicOmics : a journal of integrative biology · 2023Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Phosphoinositide 3-kinase alpha (PI3Kα) is involved in fundamental cellular processes including 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 substitution 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 PI3Kα activity, which can lead to oncogenesis. To assess the mechanism of the PI3Kα E545K activating mutation, extensive Molecular Dynamics simulations were performed to examine conformational changes differing between the wild type (WT) and mutant proteins as they occur in microsecond simulations. In the E545K mutant PI3Kα, we observe a spontaneous detachment of the nSH2 PI3Kα domain (regulatory subunit, p85α) from the helical domain (catalytic subunit, p110α) causing 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 important for delivering communication signals between the catalytic and regulatory subunits. Our results demonstrate the dynamical and structural effects induced by the p110α E545K mutation in atomic level detail and indicate a possible mechanism for the loss of regulation that E545K confers on PI3Kα.
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