ArticleScience advances2017
A dynamic hydrophobic core orchestrates allostery in protein kinases.
Article in Science advances, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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Who cites it
77 citing papers in PubMed.
- Network analysis of correlated conformational dynamics across the evolution of influenza A virus NS1.bioRxiv : the preprint server for biology · 2026Article
- Decoding the allosteric grammar of protein kinases: A dual-stream framework integrating protein language models and energy landscape frustration analysis.Protein science : a publication of the Protein Society · 2026Article
- Surface electrostatic networks control hydrophobic core remodeling in a pH-dependent switching protein.bioRxiv : the preprint server for biology · 2026Article
- Allosteric network of dynamic coupling within BAP1-UCH revealed by methyl NMR.Nature communications · 2026Article
- The Power of Protein Dynamics in Binding and Allostery.Biochemistry · 2026Review
- Saturation mutagenesis identifies activating and resistance-inducing FGFR kinase domain mutations.Nature genetics · 2026Article
- Protein Kinase A Phosphorylates a Conformationally High-energy State of Raf Kinase Inhibitory Protein.Journal of molecular biology · 2025Article
- Structural insights of AKT and its activation mechanism for drug development.Molecular diversity · 2025Review
- Local and distal changes in dynamics are caused by an L205R Cushing's syndrome mutant in PRKACA.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- PIM-1L Kinase Binds to and Inactivates SRPK1: A Biochemical and Molecular Dynamics Study.Proteins · 2025Article
- Evolutionary rewiring of the dynamic network underpinning allosteric epistasis in NS1 of the influenza A virus.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- An NMR sample preparation case study: Considerations for the self-destructive protease caspase-6.PloS one · 2025Article
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- CDK2 and CDK4: Cell Cycle Functions Evolve Distinct, Catalysis-Competent Conformations, Offering Drug Targets.JACS Au · 2024Article
- Revealing eEF-2 kinase: recent structural insights into function.Trends in biochemical sciences · 2024Review
- An update on evolutionary, structural, and functional studies of receptor-like kinases in plants.Frontiers in plant science · 2024Review
- Protein Kinase Structure and Dynamics: Role of the αC-β4 Loop.bioRxiv : the preprint server for biology · 2023Article
- Polypeptide Substrate Accessibility Hypothesis: Gain-of-Function R206H Mutation Allosterically Affects Activin Receptor-like Protein Kinase Activity.Biomolecules · 2023Article
- An NMR portrait of functional and dysfunctional allosteric cooperativity in cAMP-dependent protein kinase A.FEBS letters · 2023Review
17 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors.
Funding
Abstract
Eukaryotic protein kinases (EPKs) constitute a class of allosteric switches that mediate a myriad of signaling events. It has been postulated that EPKs' active and inactive states depend on the structural architecture of their hydrophobic cores, organized around two highly conserved spines: C-spine and R-spine. How the spines orchestrate the transition of the enzyme between catalytically uncommitted and committed states remains elusive. Using relaxation dispersion nuclear magnetic resonance spectroscopy, we found that the hydrophobic core of the catalytic subunit of protein kinase A, a prototypical and ubiquitous EPK, moves synchronously to poise the C subunit for catalysis in response to binding adenosine 5'-triphosphate. In addition to completing the C-spine, the adenine ring fuses the β structures of the N-lobe and the C-lobe. Additional residues that bridge the two spines (I150 and V104) are revealed as part of the correlated hydrophobic network; their importance was validated by mutagenesis, which led to inactivation. Because the hydrophobic architecture of the catalytic core is conserved throughout the EPK superfamily, the present study suggests a universal mechanism for dynamically driven allosteric activation of kinases mediated by coordinated signal transmission through ordered motifs in their hydrophobic cores.
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