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Published on: June 7, 2019
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Uncoupling Catalytic and Binding Functions in the Cyclic AMP-Dependent Protein Kinase A
Jonggul Kim1, Geoffrey Li2, Michael A Walters3
1Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
Structure (London, England : 1993)
|February 3, 2016
Summary
Researchers found a way to separate the dual functions of kinases by altering allosteric binding cooperativity. This discovery in protein kinase A (PKA) could lead to more selective kinase inhibitor design.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Kinases possess canonical signaling roles and non-canonical scaffolding functions.
- Uncoupling these dual roles is challenging but crucial for targeted therapies.
Purpose of the Study:
- To demonstrate a novel method for uncoupling kinase dual functions by modulating allosteric binding cooperativity.
- To investigate this concept using the C subunit of protein kinase A (PKA-C).
Main Methods:
- Utilized thermocalorimetry and nuclear magnetic resonance (NMR) spectroscopy.
- Analyzed the relationship between allosteric cooperativity and the conformational state of PKA-C.
Main Results:
- A linear correlation was observed between cooperativity and the closed state population of PKA-C.
- Non-hydrolyzable ATP analog (ATPγC) and inhibitors (H89, balanol) showed uncoupled functions, indicating altered allosteric mechanisms.
- The uncoupling mechanism is not conserved across different kinases.
Conclusions:
- Allosteric cooperativity can be tuned to uncouple kinase dual functions.
- This approach offers a new strategy for designing selective kinase inhibitors.
- Findings may impact drug development for diseases involving kinase dysregulation.
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