ArticlePhysical chemistry chemical physics : PCCP2019
The structural basis for Ras activation of PI3Kα lipid kinase.
Article in Physical chemistry chemical physics : PCCP, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
47 citing papers in PubMed, 76 citations in OpenAlex.
- Oncogenic PI3Kα variants reveal graded conformational spectrum with mutation-specific cryptic pockets.Communications chemistry · 2026Article
- NRas Nanoclusters Mediate Crosstalk Between BRAF/ERK and PI3K/AKT Signaling in Melanoma Cells.International journal of molecular sciences · 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
- Kinase signaling cascades: an updated mechanistic landscape.Chemical science · 2025Review
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- Article
- Biomarkers for colorectal cancer detection: An insight into colorectal cancer and FDA-approved biomarkers.BioImpacts : BI · 2025Review
- Molecular Basis of Oncogenic PI3K Proteins.Cancers · 2024Review
- Free energy landscape of the PI3Kα C-terminal activation.Computational and structural biotechnology journal · 2024Article
- Ras, RhoA, and vascular pharmacology in neurodevelopment and aging.Neurochemistry international · 2024Review
- AKT kinases as therapeutic targets.Journal of experimental & clinical cancer research : CR · 2024Review
- Heat shock proteins as hallmarks of cancer: insights from molecular mechanisms to therapeutic strategies.Journal of hematology & oncology · 2024Review
- Targeting Oral Cancer: In Silico Docking Studies of Phytochemicals on Oncogenic Molecular Markers.Asian Pacific journal of cancer prevention : APJCP · 2024Article
- Article
- Membrane-Driven Dimerization of the Peripheral Membrane Protein KRAS: Implications for Downstream Signaling.International journal of molecular sciences · 2024Review
- K-Ras(V12) differentially affects the three Akt isoforms in lung and pancreatic carcinoma cells and upregulates E-cadherin and NCAM via Akt3.Cell communication and signaling : CCS · 2024Article
- Mediating kinase activity in Ras-mutant cancer: potential for an individualised approach?Frontiers in pharmacology · 2024Review
- Spontaneous signal generation by an excitable system for cell migration.Frontiers in cell and developmental biology · 2024Review
- Protein conformational ensembles in function: roles and mechanisms.RSC chemical biology · 2023Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors at 1 institution in 2 countries.
Funding
Abstract
PI3Kα is a principal Ras effector that phosphorylates PIP2 to PIP3 in the PI3K/Akt/mTOR pathway. How Ras activates PI3K has been unclear: is Ras' role confined to PI3K recruitment to the membrane or does Ras activation also involve allostery? Recently, we determined the mechanism of PI3Kα activation at the atomic level. We showed the vital role and significance of conformational change in PI3Kα activation. Here, by a 'best-match for hydrogen-bonding pair' (BMHP) computational protocol and molecular dynamics (MD) simulations, we model the atomic structure of KRas4B in complex with the Ras binding domain (RBD) of PI3Kα, striving to understand the mechanism of PI3Kα activation by Ras. Point mutations T208D, K210E, and K227E disrupt the KRas4B-RBD interface in the models, in line with the experiments. We identify allosteric signaling pathways connecting Ras to RBD in the p110α subunit. However, the observed weak allosteric signals coupled with the detailed mechanism of PI3Kα activation make us conclude that the dominant mechanistic role of Ras is likely to be recruitment and restriction of the PI3Kα population at the membrane. Thus, RTK recruits the PI3Kα to the membrane and activates it by relieving its autoinhibition exerted by the nSH2 domain, leading to exposure of the kinase domain, which permits PIP2 binding. Ras recruitment can shift the PI3Kα ensemble toward a population where the kinase domain surface and the active site position and orientation favor PIP2 insertion. This work helps elucidate Ras-mediated PI3K activation and explores the structural basis for Ras-PI3Kα drug discovery.
Indexed as
Identifiers
What OpenQuestion holds
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.