ArticleProceedings of the National Academy of Sciences of the United States of America2013
Transitions to catalytically inactive conformations in 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 102 papers.
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Who cites it
102 citing papers in PubMed, 220 citations in OpenAlex.
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- 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
- Evolutionary sequence and structural basis for the distinct conformational landscapes of Tyr and Ser/Thr kinases.Nature communications · 2024Article
- Evolutionary sequence and structural basis for the distinct conformational landscapes of Tyr and Ser/Thr kinases.Research square · 2024Article
- Evolutionary sequence and structural basis for the distinct conformational landscapes of Tyr and Ser/Thr kinases.bioRxiv : the preprint server for biology · 2024Article
- Approximating Projections of Conformational Boltzmann Distributions with AlphaFold2 Predictions: Opportunities and Limitations.Journal of chemical theory and computation · 2024Article
- Molecular Dynamics and Machine Learning Give Insights on the Flexibility-Activity Relationships in Tyrosine Kinome.Journal of chemical information and modeling · 2023Article
- Approximating conformational Boltzmann distributions with AlphaFold2 predictions.bioRxiv : the preprint server for biology · 2023Article
- Molecular Simulations of Conformational Transitions within the Insulin Receptor Kinase Reveal Consensus Features in a Multistep Activation Pathway.The journal of physical chemistry. B · 2023Article
- Structural mechanism of a drug-binding process involving a large conformational change of the protein target.Nature communications · 2023Article
- Structure-Guided Strategies of Targeted Therapies for Patients withBiomolecules · 2023Review
42 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The epidermal growth factor receptor (EGFR) is a key protein in cellular signaling, and its kinase domain (EGFR kinase) is an intensely pursued target of small-molecule drugs. Although both catalytically active and inactive conformations of EGFR kinase have been resolved crystallographically, experimental characterization of the transitions between these conformations remains difficult. Using unbiased, all-atom molecular dynamics simulations, we observed EGFR kinase spontaneously transition from the active to the so-called "Src-like inactive" conformation by way of two sets of intermediate conformations: One corresponds to a previously identified locally disordered state and the other to previously undescribed "extended" conformations, marked by the opening of the ATP-binding site between the two lobes of the kinase domain. We also simulated the protonation-dependent transition of EGFR kinase to another ["Asp-Phe-Gly-out" ("DFG-out")] inactive conformation and observed similar intermediate conformations. A key element observed in the simulated transitions is local unfolding, or "cracking," which supports a prediction of energy landscape theory. We used hydrogen-deuterium (H/D) exchange measurements to corroborate our simulations and found that the simulated intermediate conformations correlate better with the H/D exchange data than existing active or inactive EGFR kinase crystal structures. The intermediate conformations revealed by our simulations of the transition process differ significantly from the existing crystal structures and may provide unique possibilities for structure-based drug discovery.
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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.