ArticleProceedings of the National Academy of Sciences of the United States of America2023
Gatekeeper mutations activate FGF receptor tyrosine kinases by destabilizing the autoinhibited state.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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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.
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Who cites it
7 citing papers in PubMed.
- Article
- Discovery of a covalent FGFR2-selective inhibitor overcoming clinically-acquired resistance mutations.Nature communications · 2026Article
- Can Deep Learning Blind Docking Methods be Used to Predict Allosteric Compounds?Journal of chemical information and modeling · 2025Article
- Spatial and signaling overlap of growth factor receptor systems at clathrin-coated sites.Molecular biology of the cell · 2024Article
- Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies.MedComm · 2024Review
- Perspectives on Computational Enzyme Modeling: From Mechanisms to Design and Drug Development.ACS omega · 2024Review
- Polypeptide Substrate Accessibility Hypothesis: Gain-of-Function R206H Mutation Allosterically Affects Activin Receptor-like Protein Kinase Activity.Biomolecules · 2023Article
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
Many types of human cancers are being treated with small molecule ATP-competitive inhibitors targeting the kinase domain of receptor tyrosine kinases. Despite initial successful remission, long-term treatment almost inevitably leads to the emergence of drug resistance mutations at the gatekeeper residue hindering the access of the inhibitor to a hydrophobic pocket at the back of the ATP-binding cleft. In addition to reducing drug efficacy, gatekeeper mutations elevate the intrinsic activity of the tyrosine kinase domain leading to more aggressive types of cancer. However, the mechanism of gain-of-function by gatekeeper mutations is poorly understood. Here, we characterized fibroblast growth factor receptor (FGFR) tyrosine kinases harboring two distinct gatekeeper mutations using kinase activity assays, NMR spectroscopy, bioinformatic analyses, and MD simulations. Our data show that gatekeeper mutations destabilize the autoinhibitory conformation of the DFG motif locally and of the kinase globally, suggesting they impart gain-of-function by facilitating the kinase's ability to populate the active state.
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