ArticleeLife2024
The αC-β4 loop controls the allosteric cooperativity between nucleotide and substrate in the catalytic subunit of protein kinase A.
Article in eLife, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- A PKA-selective inhibitor captures an open but more ordered conformation of the PKA catalytic subunit.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Allosteric binding cooperativity in kinases signaling, signalopathies, and drug development.Current opinion in structural biology · 2025Review
- Structure and Dynamics of the Misfolding Intermediate in the Pathogenic T183A Prion Protein Mutant.Journal of chemical theory and computation · 2025Article
- A structure-based tool to interpret the significance of kinase mutations in clinical next generation sequencing in cancer.Frontiers in oncology · 2025Article
- Article
- Allosteric activation of the co-receptor BAK1 by the EFR receptor kinase initiates immune signaling.eLife · 2024Article
- Protein Kinase Structure and Dynamics: Role of the αC-β4 Loop.bioRxiv : the preprint server for biology · 2023Article
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Authors and funding
11 authors.
Funding
Abstract
Allosteric cooperativity between ATP and substrates is a prominent characteristic of the cAMP-dependent catalytic subunit of protein kinase A (PKA-C). This long-range synergistic action is involved in substrate recognition and fidelity, and it may also regulate PKA's association with regulatory subunits and other binding partners. To date, a complete understanding of this intramolecular mechanism is still lacking. Here, we integrated NMR(Nuclear Magnetic Resonance)-restrained molecular dynamics simulations and a Markov State Model to characterize the free energy landscape and conformational transitions of PKA-C. We found that the apoenzyme populates a broad free energy basin featuring a conformational ensemble of the active state of PKA-C (ground state) and other basins with lower populations (excited states). The first excited state corresponds to a previously characterized inactive state of PKA-C with the αC helix swinging outward. The second excited state displays a disrupted hydrophobic packing around the regulatory (R) spine, with a flipped configuration of the F100 and F102 residues at the αC-β4 loop. We validated the second excited state by analyzing the F100A mutant of PKA-C, assessing its structural response to ATP and substrate binding. While PKA-C
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