ArticleChemical science2024
The allosteric mechanism of mTOR activation can inform bitopic inhibitor optimization.
Article in Chemical science, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 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.
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
16 citing papers in PubMed, 22 citations in OpenAlex.
- Cyclin-E/A/CDK1/2 Kinetic Landscapes Drive Cell Cycle Phase-Specific Progression and Guide Cyclin-E Degradation Strategy.Journal of chemical information and modeling · 2026Article
- Leveraging conformational ensembles in allosteric drug discovery.Trends in pharmacological sciences · 2026Review
- Oncogenic PI3Kα variants reveal graded conformational spectrum with mutation-specific cryptic pockets.Communications chemistry · 2026Article
- The structural heterogeneity of AKT autoinhibition.Protein science : a publication of the Protein Society · 2026Article
- ERK Allosteric Activation: The Importance of Two Ordered Phosphorylation Events.Journal of molecular biology · 2025Article
- Resistance to Allosteric Inhibitors.Journal of molecular biology · 2025Review
- 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
- Exploring serum and glucocorticoid-regulated kinase 1: A promising target for COVID-19 and atrial fibrillation treatment.Heart rhythm O2 · 2025Review
- Substituents introduction of methyl and methoxy functional groups on resveratrol stabilizes mTOR binding for autophagic cell death induction.Scientific reports · 2025Article
- Molecular principles underlying aggressive cancers.Signal transduction and targeted therapy · 2025Review
- Allosteric modulation of NF1 GAP: Differential distributions of catalytically competent populations in loss-of-function and gain-of-function mutants.Protein science : a publication of the Protein Society · 2025Article
- mTOR Variants Activation Discovers PI3K-like Cryptic Pocket, Expanding Allosteric, Mutant-Selective Inhibitor Designs.Journal of chemical information and modeling · 2025Article
- Making PI3K superfamily enzymes run faster.Advances in biological regulation · 2025Review
- Capturing Autoinhibited PDK1 Reveals the Linker's Regulatory Role, Informing Innovative Inhibitor Design.Journal of chemical information and modeling · 2024Article
- The value of protein allostery in rational anticancer drug design: an update.Expert opinion on drug discovery · 2024Review
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
mTOR serine/threonine kinase is a cornerstone in the PI3K/AKT/mTOR pathway. Yet, the detailed mechanism of activation of its catalytic core is still unresolved, likely due to mTOR complexes' complexity. Its dysregulation was implicated in cancer and neurodevelopmental disorders. Using extensive molecular dynamics (MD) simulations and compiled published experimental data, we determine exactly how mTOR's inherent motifs can control the conformational changes in the kinase domain, thus kinase activity. We also chronicle the critical regulation by the unstructured negative regulator domain (NRD). When positioned inside the catalytic cleft (NRD IN state), mTOR tends to adopt a deep and closed catalytic cleft. This is primarily due to the direct interaction with the FKBP-rapamycin binding (FRB) domain which restricts it, preventing substrate access. Conversely, when outside the catalytic cleft (NRD OUT state), mTOR favors an open conformation, exposing the substrate-binding site on the FRB domain. We further show how an oncogenic mutation (L2427R) promotes shifting the mTOR ensemble toward the catalysis-favored state. Collectively, we extend mTOR's "active-site restriction" mechanism and clarify mutation action. In particular, our mechanism suggests that RMC-5552 (RMC-6272) bitopic inhibitors may benefit from adjustment of the (PEG
Identifiers
What Socratic 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 Socratic graph.