ArticleScience advances2020
Allosteric pluripotency as revealed by protein kinase A.
Article in Science advances, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 42 citations in OpenAlex.
- Functional divergence of protein kinase A regulatory subunit Iβ variants: the importance of N3A motifs in PKA regulation.The FEBS journal · 2026Article
- Recurrent Acrodysostosis-Related PKA RIα Mutant Reveals a Novel Mechanism of Aberrant PKA Deactivation.Journal of molecular biology · 2025Article
- Purine nucleosides replace cAMP in allosteric regulation of PKA in trypanosomatid pathogens.eLife · 2024Article
- Mixed, nonclassical behavior in a classic allosteric protein.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Conformational changes in protein kinase A along its activation cycle are rooted in the folding energetics of cyclic-nucleotide binding domains.The Journal of biological chemistry · 2023Article
- An NMR portrait of functional and dysfunctional allosteric cooperativity in cAMP-dependent protein kinase A.FEBS letters · 2023Review
- Article
- Allostery, and how to define and measure signal transduction.Biophysical chemistry · 2022Review
- Molecular mechanism of glycolytic flux control intrinsic to human phosphoglycerate kinase.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- State-selective frustration as a key driver of allosteric pluripotency.Chemical science · 2021Article
- Noncanonical protein kinase A activation by oligomerization of regulatory subunits as revealed by inherited Carney complex mutations.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Article
- Allosteric Mechanisms of Nonadditive Substituent Contributions to Protein-Ligand Binding.Biophysical journal · 2020Article
- Allosteric inhibition explained through conformational ensembles sampling distinct "mixed" states.Computational and structural biotechnology journal · 2020Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
The functional response of a signaling system to an allosteric stimulus often depends on subcellular conditions, a phenomenon known as pluripotent allostery. For example, a single allosteric modulator, Rp-cAMPS, of the prototypical protein kinase A (PKA) switches from antagonist to agonist depending on MgATP levels. However, the mechanism underlying such pluripotent allostery has remained elusive for decades. Using nuclear magnetic resonance spectroscopy, ensemble models, kinase assays, and molecular dynamics simulations, we show that allosteric pluripotency arises from surprisingly divergent responses of highly homologous tandem domains. The differential responses perturb domain-domain interactions and remodel the free-energy landscape of inhibitory excited states sampled by the regulatory subunit of PKA. The resulting activation threshold values are comparable to the effective free energy of regulatory and catalytic subunit binding, which depends on metabolites, substrates, and mutations, explaining pluripotent allostery and warranting a general redefinition of allosteric targets to include specific subcellular environments.
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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.