ArticleeLife2017
Elucidation of a four-site allosteric network in fibroblast growth factor receptor tyrosine kinases.
Article in eLife, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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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.
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Who cites it
29 citing papers in PubMed.
- Recurrent Resistance Mutations to Lirafugratinib Inform Treatment Sequencing in FGFR2-Driven Tumors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Trial
- Article
- Review
- Elucidating the Role of Wildtype and Variant FGFR2 Structural Dynamics in (Dys)Function and Disorder.International journal of molecular sciences · 2024Article
- FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions.Nature reviews. Clinical oncology · 2024Review
- The molecular interaction pattern of lenvatinib enables inhibition of wild-type or kinase-mutated FGFR2-driven cholangiocarcinoma.Nature communications · 2024Article
- Gatekeeper mutations activate FGF receptor tyrosine kinases by destabilizing the autoinhibited state.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Analysis of coordinated NMR chemical shifts to map allosteric regulatory networks in proteins.Methods (San Diego, Calif.) · 2023Article
- Signaling pathways and targeted therapies in lung squamous cell carcinoma: mechanisms and clinical trials.Signal transduction and targeted therapy · 2022Review
- Identification of core allosteric sites through temperature- and nucleus-invariant chemical shift covariance.Biophysical journal · 2022Article
- Review
- Kincore: a web resource for structural classification of protein kinases and their inhibitors.Nucleic acids research · 2022Article
- Fibroblast growth factor receptor fusions in cancer: opportunities and challenges.Journal of experimental & clinical cancer research : CR · 2021Review
- Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer.NPJ precision oncology · 2021Article
- CHESPA/CHESCA-SPARKY: automated NMR data analysis plugins for SPARKY to map protein allostery.Bioinformatics (Oxford, England) · 2021Article
- Temperature-dependent autoactivation associated with clinical variability of PDGFRB Asn666 substitutions.Human molecular genetics · 2021Article
- Conformational states dynamically populated by a kinase determine its function.Science (New York, N.Y.) · 2020Article
- Allosteric Mechanisms of Nonadditive Substituent Contributions to Protein-Ligand Binding.Biophysical journal · 2020Article
- Molecular basis for receptor tyrosine kinase A-loop tyrosine transphosphorylation.Nature chemical biology · 2020Article
- Identification of a novel oncogenic mutation of FGFR4 in gastric cancer.Scientific reports · 2019Article
Corrections and comments
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Authors and funding
11 authors.
Funding
Abstract
Receptor tyrosine kinase (RTK) signaling is tightly regulated by protein allostery within the intracellular tyrosine kinase domains. Yet the molecular determinants of allosteric connectivity in tyrosine kinase domain are incompletely understood. By means of structural (X-ray and NMR) and functional characterization of pathogenic gain-of-function mutations affecting the FGF receptor (FGFR) tyrosine kinase domain, we elucidated a long-distance allosteric network composed of four interconnected sites termed the 'molecular brake', 'DFG latch', 'A-loop plug', and 'αC tether'. The first three sites repress the kinase from adopting an active conformation, whereas the αC tether promotes the active conformation. The skewed design of this four-site allosteric network imposes tight autoinhibition and accounts for the incomplete mimicry of the activated conformation by pathogenic mutations targeting a single site. Based on the structural similarity shared among RTKs, we propose that this allosteric model for FGFR kinases is applicable to other RTKs.
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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.