ArticleStructure (London, England : 1993)2019
A Conserved Allosteric Pathway in Tyrosine Kinase Regulation.
Article in Structure (London, England : 1993), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Review
- α, δ‑ACS pharmacology & translational science · 2025Article
- FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions.Nature reviews. Clinical oncology · 2024Review
- Landscape of Clinical Resistance Mechanisms to FGFR Inhibitors in FGFR2-Altered Cholangiocarcinoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice.JCI insight · 2023Article
- 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
- Probing conformational landscapes and mechanisms of allosteric communication in the functional states of the ABL kinase domain using multiscale simulations and network-based mutational profiling of allosteric residue potentials.The Journal of chemical physics · 2022Article
- Membrane Hormone Receptors and Their Signaling Pathways as Targets for Endocrine Disruptors.Journal of xenobiotics · 2022Review
- The Inherent Coupling of Intrinsically Disordered Regions in the Multidomain Receptor Tyrosine Kinase KIT.International journal of molecular sciences · 2022Article
- Fibroblast growth factor receptor fusions in cancer: opportunities and challenges.Journal of experimental & clinical cancer research : CR · 2021Review
- Defective internal allosteric network imparts dysfunctional ATP/substrate-binding cooperativity in oncogenic chimera of protein kinase A.Communications biology · 2021Article
- Allosteric pluripotency as revealed by protein kinase A.Science advances · 2020Article
Corrections and comments
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Authors and funding
6 authors.
Funding
Abstract
An autoinhibitory network of hydrogen bonds located at the kinase hinge (referred to as the "molecular brake") regulates the activity of several receptor tyrosine kinases. The mechanism whereby mutational disengagement of the brake allosterically activates the kinase in human disease is incompletely understood. We used a combination of NMR, bioinformatics, and molecular dynamics simulation to show that mutational disruption of the molecular brake triggers localized conformational perturbations that propagate to the active site. This entails changes in interactions of an isoleucine, one of three hydrophobic residues that lock the phenylalanine of the DFG motif in an inactive conformation. Structural analysis of tyrosine kinases provides evidence that this allosteric control mechanism is shared across the tyrosine kinase family. We also show that highly activating mutations at the brake diminish the enzyme's thermostability, thereby explaining why these mutations cause milder skeletal syndromes compared with less-activating mutations in the activation loop.
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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.