ArticleProceedings of the National Academy of Sciences of the United States of America2022
Cryo-EM structures of cancer-specific helical and kinase domain mutations of PI3Kα.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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26 citing papers in PubMed, 47 citations in OpenAlex.
- Commentary beyond the ATP site: Cryo-EM views of allosteric PI3KActa pharmaceutica Sinica. B · 2026Article
- Molecular architecture responsible for specific inhibition of oncogenic PI3KActa pharmaceutica Sinica. B · 2026Article
- Structures of the PI3Kα/KRas complex on lipid bilayers reveal molecular mechanisms of PI3Kα activation.Molecular cell · 2026Article
- De novo design of anticancer 4-thiazolidinone derivatives: a generative framework shaped by activity cliffs.Journal of cheminformatics · 2026Article
- Use of hydrogen deuterium exchange mass spectrometry in tandem with modern structural biology.The Biochemical journal · 2026Review
- Synthesis, structural characterization and molecular docking analysis of novel β-ketoiminato palladium(ii) complexes with anticancer properties.RSC advances · 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
- Cryo-EM ligand building using AlphaFold3-like model and molecular dynamics.PLoS computational biology · 2025Article
- Oncogenic activation ofGenes & diseases · 2025Review
- Clinical, genomic, and histopathologic diversity in cerebral cavernous malformations.Acta neuropathologica communications · 2025Article
- Co-expression of the RPS6KB1 and PDPK1 genes for production of activated p70S6K1 using bac-to-bac baculovirus expression system.Molecular biology reports · 2025Article
- Making PI3K superfamily enzymes run faster.Advances in biological regulation · 2025Review
- Molecular Basis of Oncogenic PI3K Proteins.Cancers · 2024Review
- Free energy landscape of the PI3Kα C-terminal activation.Computational and structural biotechnology journal · 2024Article
- Discovery of Pyridopyrimidinones that Selectively Inhibit the H1047R PI3Kα Mutant Protein.Journal of medicinal chemistry · 2024Article
- Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3Kα Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia.Cancer discovery · 2024Article
- Exploring the Therapeutic Potential ofCurrent drug discovery technologies · 2024Article
- Structural and mechanistic insights provided by single particle cryo-EM analysis of phosphoinositide 3-kinase (PI3Kα).Biochimica et biophysica acta. Reviews on cancer · 2023Review
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8 authors at 3 institutions in 3 countries.
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Abstract
Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that perform multiple and important cellular functions. The protein investigated here belongs to class IA of the PI3Ks; it is a dimer consisting of a catalytic subunit, p110α, and a regulatory subunit, p85α, and is referred to as PI3Kα. The catalytic subunit p110α is frequently mutated in cancer. The mutations induce a gain of function and constitute a driving force in cancer development. About 80% of these mutations lead to single-amino-acid substitutions in one of three sites of p110α: two in the helical domain of the protein (E542K and E545K) and one at the C-terminus of the kinase domain (H1047R). Here, we report the cryo-electron microscopy structures of these mutants in complex with the p110α-specific inhibitor BYL-719. The H1047R mutant rotates its sidechain to a new position and weakens the kα11 activation loop interaction, thereby reducing the inhibitory effect of p85α on p110α. E542K and E545K completely abolish the tight interaction between the helical domain of p110α and the N-terminal SH2 domain of p85α and lead to the disruption of all p85α binding and a dramatic increase in flexibility of the adaptor-binding domain (ABD) in p110α. Yet, the dimerization of PI3Kα is preserved through the ABD-p85α interaction. The local and global structural features induced by these mutations provide molecular insights into the activation of PI3Kα, deepen our understanding of the oncogenic mechanism of this important signaling molecule, and may facilitate the development of mutant-specific inhibitors.
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