ArticlePLoS computational biology2014
Investigating the structure and dynamics of the PIK3CA wild-type and H1047R oncogenic mutant.
Article in PLoS computational biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 94 citations in OpenAlex.
- Mapping Mutations and Signaling Network Interactions to Guide Precision Therapy in Gallbladder Cancer.Cancer reports (Hoboken, N.J.) · 2026Review
- Molecular architecture responsible for specific inhibition of oncogenic PI3KActa pharmaceutica Sinica. B · 2026Article
- Oncogenic PIK3CA reprograms glutamine metabolism to drive bladder cancer progression.Cell communication and signaling : CCS · 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
- Understanding the conformational dynamics of PI3Kα due to helical domain mutations: insights from Markov state model analysis.Molecular diversity · 2025Article
- Structural and allosteric effects of the membrane-bound PI3Kα H1047R mutation and opportunities for drug discovery.Communications chemistry · 2025Article
- Differential Efficacy of Alpelisib by PIK3CA Mutation Site in Head and Neck Squamous Cell Carcinoma: An Analysis from the KCSG HN 15-16 TRIUMPH Trial.Cancer research and treatment · 2025Article
- Molecular mechanisms of PI3Kα activation by small-molecule activator 1938 and cancer-specific mutation H1047R.Cell discovery · 2025Article
- Review
- Combinatorial screen of targeted agents with the PI3K inhibitors inavolisib, alpelisib, duvelisib, and copanlisib in multi-cell type tumor spheroids.SLAS discovery : advancing life sciences R & D · 2025Article
- Mechanistic optimization of inavolisib combined with CDK4/6 inhibitors in the treatment of PIK3CA-mutated breast tumors.Frontiers in immunology · 2025Review
- Free energy landscape of the PI3Kα C-terminal activation.Computational and structural biotechnology journal · 2024Article
- Epinephrine inhibits PI3Kα via the Hippo kinases.Cell reports · 2023Article
- Mutational Landscape and In-Silico Analysis ofACS omega · 2023Article
- Liquid biopsy: Cell-free DNA based analysis in breast cancer.The journal of liquid biopsy · 2023Review
- Structural and mechanistic insights provided by single particle cryo-EM analysis of phosphoinositide 3-kinase (PI3Kα).Biochimica et biophysica acta. Reviews on cancer · 2023Review
- Oncogenic mutations of PIK3CA lead to increased membrane recruitment driven by reorientation of the ABD, p85 and C-terminus.Nature communications · 2023Article
- Aspirin sensitivity of PIK3CA-mutated Colorectal Cancer: potential mechanisms revisited.Cellular and molecular life sciences : CMLS · 2022Review
- Dynamic rewiring of biological activity across genotype and lineage revealed by context-dependent functional interactions.Genome biology · 2022Article
- Predicting protein-membrane interfaces of peripheral membrane proteins using ensemble machine learning.Briefings in bioinformatics · 2022Article
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The PIK3CA gene is one of the most frequently mutated oncogenes in human cancers. It encodes p110α, the catalytic subunit of phosphatidylinositol 3-kinase alpha (PI3Kα), which activates signaling cascades leading to cell proliferation, survival, and cell growth. The most frequent mutation in PIK3CA is H1047R, which results in enzymatic overactivation. Understanding how the H1047R mutation causes the enhanced activity of the protein in atomic detail is central to developing mutant-specific therapeutics for cancer. To this end, Surface Plasmon Resonance (SPR) experiments and Molecular Dynamics (MD) simulations were carried out for both wild-type (WT) and H1047R mutant proteins. An expanded positive charge distribution on the membrane binding regions of the mutant with respect to the WT protein is observed through MD simulations, which justifies the increased ability of the mutated protein variant to bind to membranes rich in anionic lipids in our SPR experiments. Our results further support an auto-inhibitory role of the C-terminal tail in the WT protein, which is abolished in the mutant protein due to loss of crucial intermolecular interactions. Moreover, Functional Mode Analysis reveals that the H1047R mutation alters the twisting motion of the N-lobe of the kinase domain with respect to the C-lobe and shifts the position of the conserved P-loop residues in the vicinity of the active site. These findings demonstrate the dynamical and structural differences of the two proteins in atomic detail and propose a mechanism of overactivation for the mutant protein. The results may be further utilized for the design of mutant-specific PI3Kα inhibitors that exploit the altered mutant conformation.
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