ArticleNature structural & molecular biology2008
Activation of tyrosine kinases by mutation of the gatekeeper threonine.
Article in Nature structural & molecular biology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 225 papers, 1 of them a synthesis that pooled it.
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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
225 citing papers in PubMed, 1 synthesis or guideline pooled it, 414 citations in OpenAlex.
- Clinical Insights into Structure, Regulation, and Targeting of ABL Kinases in Human Leukemia.International journal of molecular sciences · 2024Pooled it
- Tyrosine kinases sample unique activation ensembles.bioRxiv : the preprint server for biology · 2026Article
- Intrinsic cellular resistance to BCR::ABL1 inhibitors.Haematologica · 2026Review
- Non-Classical Binding Mechanisms of Ferrocene-Modified Imatinib and Nilotinib Analogues in BCR-ABL1 Kinase Revealed by Computational Analysis.Molecules (Basel, Switzerland) · 2026Article
- Water-Based Pharmacophore Modeling in Kinase Inhibitor Design: A Case Study on Fyn and Lyn Protein Kinases.Journal of chemical information and modeling · 2025Article
- Exploiting collateral sensitivity in the evolution of resistance to tyrosine kinase inhibitors in soft tissue sarcomas.Communications biology · 2025Article
- Prospective Evaluation of Structure-Based Simulations Reveal Their Ability to Predict the Impact of Kinase Mutations on Inhibitor Binding.The journal of physical chemistry. B · 2025Article
- Asciminib in the treatment of chronic myeloid leukemia in chronic phase.Future oncology (London, England) · 2025Review
- Prospective evaluation of structure-based simulations reveal their ability to predict the impact of kinase mutations on inhibitor binding.bioRxiv : the preprint server for biology · 2025Article
- Constitutive activation of the Src-family kinases Fgr and Hck enhances the tumor burden of acute myeloid leukemia cells in immunocompromised mice.Scientific reports · 2025Article
- A New Mechanism of Supraventricular Tachycardia: Gene Mutation.Current cardiology reviews · 2025Review
- An SH3-binding allosteric modulator stabilizes the global conformation of the AML-associated Src-family kinase, Hck.The Journal of biological chemistry · 2025Article
- Exploring the conformational landscape of protein kinases.Current opinion in structural biology · 2024Review
- AXL and SHC1 confer crizotinib resistance in patient-derived xenograft model of ALK-driven lung cancer.iScience · 2024Article
- Article
- A fluorescence-based sensor for calibrated measurement of protein kinase stability in live cells.Protein science : a publication of the Protein Society · 2024Article
- CDK2 and CDK4: Cell Cycle Functions Evolve Distinct, Catalysis-Competent Conformations, Offering Drug Targets.JACS Au · 2024Article
- Conserved regulatory motifs in the juxtamembrane domain and kinase N-lobe revealed through deep mutational scanning of the MET receptor tyrosine kinase domain.bioRxiv : the preprint server for biology · 2024Article
- Profiling of drug resistance in Src kinase at scale uncovers a regulatory network coupling autoinhibition and catalytic domain dynamics.Cell chemical biology · 2024Article
- Allo-targeting of the kinase domain: Insights from in silico studies and comparison with experiments.Current opinion in structural biology · 2024Review
165 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 4 institutions in 1 country.
Funding
Abstract
Protein kinases targeted by small-molecule inhibitors develop resistance through mutation of the 'gatekeeper' threonine residue of the active site. Here we show that the gatekeeper mutation in the cellular forms of c-ABL, c-SRC, platelet-derived growth factor receptor-alpha and -beta, and epidermal growth factor receptor activates the kinase and promotes malignant transformation of BaF3 cells. Structural analysis reveals that a network of hydrophobic interactions-the hydrophobic spine-characteristic of the active kinase conformation is stabilized by the gatekeeper substitution. Substitution of glycine for the residues constituting the spine disrupts the hydrophobic connectivity and inactivates the kinase. Furthermore, a small-molecule inhibitor that maximizes complementarity with the dismantled spine (compound 14) inhibits the gatekeeper mutation of BCR-ABL-T315I. These results demonstrate that mutation of the gatekeeper threonine is a common mechanism of activation for tyrosine kinases and provide structural insights to guide the development of next-generation inhibitors.
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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.