ArticleStructure (London, England : 1993)2016
Uncoupling Catalytic and Binding Functions in the Cyclic AMP-Dependent Protein Kinase A.
Article in Structure (London, England : 1993), 2016. 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.
- Allosteric binding cooperativity in kinases signaling, signalopathies, and drug development.Current opinion in structural biology · 2025Review
- ATP-competitive inhibitors modulate the substrate binding cooperativity of a kinase by altering its conformational entropy.Science advances · 2022Article
- Raf Kinase Inhibitory Protein regulates the cAMP-dependent protein kinase signaling pathway through a positive feedback loop.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Using Optical Tweezers to Monitor Allosteric Signals Through Changes in Folding Energy Landscapes.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Dynamic equilibria in protein kinases.Current opinion in structural biology · 2021Review
- Defective internal allosteric network imparts dysfunctional ATP/substrate-binding cooperativity in oncogenic chimera of protein kinase A.Communications biology · 2021Article
- Role of Marek's Disease Virus (MDV)-Encoded UJournal of virology · 2020Article
- Cushing's syndrome driver mutation disrupts protein kinase A allosteric network, altering both regulation and substrate specificity.Science advances · 2019Article
- Globally correlated conformational entropy underlies positive and negative cooperativity in a kinase's enzymatic cycle.Nature communications · 2019Article
- Water-mediated conformational preselection mechanism in substrate binding cooperativity to protein kinase A.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Substrate Affinity Differentially Influences Protein Kinase C Regulation and Inhibitor Potency.The Journal of biological chemistry · 2016Article
- Bimodal antagonism of PKA signalling by ARHGAP36.Nature communications · 2016Article
- cAMP-dependent protein kinase (PKA) complexes probed by complementary differential scanning fluorimetry and ion mobility-mass spectrometry.The Biochemical journal · 2016Article
- Unbiased clustering of residues undergoing synchronous motions in proteins using NMR spin relaxation data.Biophysical chemistryArticle
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
The canonical function of kinases is to transfer a phosphoryl group to substrates, initiating a signaling cascade; while their non-canonical role is to bind other kinases or substrates, acting as scaffolds, competitors, and signal integrators. Here, we show how to uncouple kinases' dual function by tuning the binding cooperativity between nucleotide (or inhibitors) and substrate allosterically. We demonstrate this new concept for the C subunit of protein kinase A (PKA-C). Using thermocalorimetry and nuclear magnetic resonance, we found a linear correlation between the degree of cooperativity and the population of the closed state of PKA-C. The non-hydrolyzable ATP analog (ATPγC) does not follow this correlation, suggesting that changing the chemical groups around the phosphoester bond can uncouple kinases' dual function. Remarkably, this uncoupling was also found for two ATP-competitive inhibitors, H89 and balanol. Since the mechanism for allosteric cooperativity is not conserved in different kinases, these results may suggest new approaches for designing selective kinase inhibitors.
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