ArticleeLife2021
Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors.
Article in eLife, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
20 citing papers in PubMed, 53 citations in OpenAlex.
- PI3Kδ is selectively inhibited by roginolisib by stabilizing the C-terminal helix kα12.Nature communications · 2026Article
- Use of hydrogen deuterium exchange mass spectrometry in tandem with modern structural biology.The Biochemical journal · 2026Review
- Fatty acid scavenging enables cancer escape from KRAS inhibition.bioRxiv : the preprint server for biology · 2026Article
- Chemical programming of kinase inhibitors in a modular chemputer-based system.Communications biology · 2026Article
- Selective phosphoinositide 3-kinase inhibitors and implication in diabetic retinopathy as pharmacological tools.Frontiers in pharmacology · 2026Review
- Enhancing PI3Kγ inhibitor discovery: a machine learning-based virtual screening approach integrating pharmacophores, docking, and molecular descriptors.Molecular diversity · 2025Article
- Computational studies on the functional and structural impact of pathogenic mutations in enzymes.Protein science : a publication of the Protein Society · 2025Review
- 1,3,4-thiadiazole derivatives as PI3Ks inhibitor: design, in silico studies, synthesis, characterization, and antimicrobial evaluation.Turkish journal of chemistry · 2025Article
- Prediction of immunotherapy response using mutations to cancer protein assemblies.Science advances · 2024Article
- LC-ESI-MS/MS-based molecular networking, antioxidant, anti-glioma activity and molecular docking studies of Clematis graveolens.Plant methods · 2024Article
- Novel 2-Aminobenzothiazole Derivatives: Docking, Synthesis, and Biological Evaluation as Anticancer Agents.ACS omega · 2024Article
- Article
- Allosteric activation or inhibition of PI3Kγ mediated through conformational changes in the p110γ helical domain.bioRxiv : the preprint server for biology · 2023Article
- Molecular basis for differential activation of p101 and p84 complexes of PI3Kγ by Ras and GPCRs.Cell reports · 2023Article
- Oncogenic mutations of PIK3CA lead to increased membrane recruitment driven by reorientation of the ABD, p85 and C-terminus.Nature communications · 2023Article
- The role of PI3Kγ in the immune system: new insights and translational implications.Nature reviews. Immunology · 2022Review
- Synthesis, Molecular Docking, In Vitro and In Vivo Studies of Novel Dimorpholinoquinazoline-Based Potential Inhibitors of PI3K/Akt/mTOR Pathway.International journal of molecular sciences · 2022Article
- Development of New Thiophene-Containing Triaryl Pyrazoline Derivatives as PI3Kγ Inhibitors.Molecules (Basel, Switzerland) · 2022Article
- Structure of the phosphoinositide 3-kinase (PI3K) p110γ-p101 complex reveals molecular mechanism of GPCR activation.Science advances · 2021Article
- Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 3 countries.
Funding
Abstract
Class I Phosphoinositide 3-kinases (PI3Ks) are master regulators of cellular functions, with the class IB PI3K catalytic subunit (p110γ) playing key roles in immune signalling. p110γ is a key factor in inflammatory diseases and has been identified as a therapeutic target for cancers due to its immunomodulatory role. Using a combined biochemical/biophysical approach, we have revealed insight into regulation of kinase activity, specifically defining how immunodeficiency and oncogenic mutations of R1021 in the C-terminus can inactivate or activate enzyme activity. Screening of inhibitors using HDX-MS revealed that activation loop-binding inhibitors induce allosteric conformational changes that mimic those in the R1021C mutant. Structural analysis of advanced PI3K inhibitors in clinical development revealed novel binding pockets that can be exploited for further therapeutic development. Overall, this work provides unique insights into regulatory mechanisms that control PI3Kγ kinase activity and shows a framework for the design of PI3K isoform and mutant selective inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.