ArticleNature chemical biology2020
Molecular basis for receptor tyrosine kinase A-loop tyrosine transphosphorylation.
Article in Nature chemical biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 53 citations in OpenAlex.
- Article
- DUSP4 activates adipocyte thermogenesis via CRTC3 dephosphorylation-dependent UCP1 expression.Experimental & molecular medicine · 2026Article
- State-Dependent FGF Signaling in Satellite Cell-Mediated Skeletal Muscle Regeneration and Pathological Remodeling.Biomolecules · 2026Review
- Discovery of a covalent FGFR2-selective inhibitor overcoming clinically-acquired resistance mutations.Nature communications · 2026Article
- A conserved dimerization element is required for protein kinase activation bybioRxiv : the preprint server for biology · 2026Article
- Saturation mutagenesis identifies activating and resistance-inducing FGFR kinase domain mutations.Nature genetics · 2026Article
- Design and synthesis of an erdafitinib-based selective FGFR2 degrader.Beilstein journal of organic chemistry · 2026Article
- Research on Targeted Therapy for Malignant Tumors of the Biliary Tract.OncoTargets and therapy · 2026Review
- Mutation in IR or IGF1R produces features of long-lived mice while maintaining metabolic health.JCI insight · 2025Article
- Impact of the changes in substrate specificity of herpes simplex virus 1 protein kinase Us3 on viral infectionJournal of virology · 2025Article
- FGF-based drug discovery: advances and challenges.Nature reviews. Drug discovery · 2025Review
- Synthetic transmembrane DNA receptors enable engineered sensing and actuation.Nature communications · 2025Article
- Cell-free expression and SMA copolymer encapsulation of a functional receptor tyrosine kinase disease variant, FGFR3-TACC3.Scientific reports · 2025Article
- Electrical Forces Improve Memory in Old Age.Reviews of physiology, biochemistry and pharmacology · 2025Review
- Probing phosphorylation events in biological membranes: The transducer function.Biochimica et biophysica acta. Biomembranes · 2024Review
- 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
- EWS/FLI1 Characterization, Activation, Repression, Target Genes and Therapeutic Opportunities in Ewing Sarcoma.International journal of molecular sciences · 2023Review
- A critical evaluation of protein kinase regulation by activation loop autophosphorylation.eLife · 2023Article
- The combined action of the intracellular regions regulates FGFR2 kinase activity.Communications biology · 2023Article
- Structural basis for FGF hormone signalling.Nature · 2023Article
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 2 countries.
Funding
Abstract
A long-standing mystery shrouds the mechanism by which catalytically repressed receptor tyrosine kinase domains accomplish transphosphorylation of activation loop (A-loop) tyrosines. Here we show that this reaction proceeds via an asymmetric complex that is thermodynamically disadvantaged because of an electrostatic repulsion between enzyme and substrate kinases. Under physiological conditions, the energetic gain resulting from ligand-induced dimerization of extracellular domains overcomes this opposing clash, stabilizing the A-loop-transphosphorylating dimer. A unique pathogenic fibroblast growth factor receptor gain-of-function mutation promotes formation of the complex responsible for phosphorylation of A-loop tyrosines by eliminating this repulsive force. We show that asymmetric complex formation induces a more phosphorylatable A-loop conformation in the substrate kinase, which in turn promotes the active state of the enzyme kinase. This explains how quantitative differences in the stability of ligand-induced extracellular dimerization promotes formation of the intracellular A-loop-transphosphorylating asymmetric complex to varying extents, thereby modulating intracellular kinase activity and signaling intensity.
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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.