ArticleProceedings of the National Academy of Sciences of the United States of America2013
Effects of oncogenic mutations on the conformational free-energy landscape of EGFR kinase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 93 papers.
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Who cites it
93 citing papers in PubMed.
- Diacerein Protects Against Obesity-Related Cardiovascular Injury: Evidence from In Silico and In Vivo Studies.Applied biochemistry and biotechnology · 2026Article
- Article
- From Descriptor Learning to Binding Stability: An Explainable Machine Learning Pipeline for EGFR Double-Mutant Inhibitor Discovery.International journal of molecular sciences · 2026Article
- Tyrosine kinases sample unique activation ensembles.bioRxiv : the preprint server for biology · 2026Article
- Integrated in silico and in vitro assessment of Azadirachta indica leaf extract against multi-drug resistant Citrobacter koseri and Staphylococcus saprophyticus.Scientific reports · 2026Article
- Integrative structural and dynamics studies of epidermal growth factor receptor (EGFR).Experimental & molecular medicine · 2026Review
- A Transferable and Robust Computational Framework for Class A GPCR Activation Free Energies.The journal of physical chemistry letters · 2026Article
- Osimertinib's Proton-Catalyzed, Pseudoconcerted EGFR Inhibition Guides Next-Generation Inhibitor Design.Journal of chemical information and modeling · 2026Article
- The Effects of Variant Allele Frequency for EGFR Mutation on Early Tumor Shrinkage and Deepness of Response to Osimertinib in Patients with Metastatic Non-Small Cell Lung Cancer: An Exploratory Analysis.Journal of clinical medicine · 2026Article
- Deciphering the Structural Basis of Allosteric Inhibition of Mutant Epidermal Growth Factor Receptor and Identification of Novel Inhibitors.Computational and structural biotechnology journal · 2026Article
- Enhanced Sampling and Tailored Collective Variables Yield Reproducible Free Energy Landscapes of Beta-1 Adrenergic Receptor Activation.Journal of chemical theory and computation · 2025Article
- Conformational Remodeling and Allosteric Regulation Underlying EGFR Mutant-Induced Activation: A Multi-Scale Analysis Using MD, MSMs, and NRI.International journal of molecular sciences · 2025Article
- Design and investigation of novel iridoid-based peptide conjugates for targeting EGFR and its mutants L858R and T790M/L858R/C797S: an in silico study.Molecular diversity · 2025Article
- Structure-guided discovery and characterization of novel FLT3 inhibitors for acute myeloid leukemia treatment.PloS one · 2025Article
- Coupling enzymatic digestion with nanopore sensing for low-abundance EGFR-L858R mutation detection.Frontiers in bioengineering and biotechnology · 2025Article
- A molecular dynamics protocol for rapid prediction of EGFR overactivation and its application to the rare mutations S768I, S768N, D761N.Computational and structural biotechnology journal · 2025Article
- Absolute Binding Free Energies with OneOPES.The journal of physical chemistry letters · 2024Article
- Signaling dynamics in coexisting monoclonal cell subpopulations unveil mechanisms of resistance to anti-cancer compounds.Cell communication and signaling : CCS · 2024Article
- Drug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers.Nature communications · 2024Article
- Structure-activity exploration of a small-molecule allosteric inhibitor of T790M/L858R double mutant EGFR.Journal of enzyme inhibition and medicinal chemistry · 2023Article
33 more citing papers are in PubMed but not listed here.
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2 authors.
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Abstract
Activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase are frequently found in many cancers. It has been suggested that changes in the equilibrium between its active and inactive conformations are linked to its oncogenic potential. Here, we quantify the effects of some of the most common single (L858R and T790M) and double (T790M-L858R) oncogenic mutations on the conformational free-energy landscape of the EGFR kinase domain by using massive molecular dynamics simulations together with parallel tempering, metadynamics, and one of the best force-fields available. Whereas the wild-type EGFR catalytic domain monomer is mostly found in an inactive conformation, our results show a clear shift toward the active conformation for all of the mutants. The L858R mutation stabilizes the active conformation at the expense of the inactive conformation and rigidifies the αC-helix. The T790M gatekeeper mutant favors activation by stabilizing a hydrophobic cluster. Finally, T790M with L858R shows a significant positive epistasis effect. This combination not only stabilizes the active conformation, but in nontrivial ways changes the free-energy landscape lowering the transition barriers.
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