ArticleBiochemistry2017
Electrostatic Interactions as Mediators in the Allosteric Activation of Protein Kinase A RIα.
Article in Biochemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Geometric Deep Learning-Based Drug Design Models for Small-Molecule Drug Discovery.Molecular informatics · 2026Review
- Surface electrostatic networks control hydrophobic core remodeling in a pH-dependent switching protein.bioRxiv : the preprint server for biology · 2026Article
- A divergent protein kinase A regulatory subunit essential for morphogenesis of the human pathogen Leishmania.PLoS pathogens · 2024Article
- Discovery and Synthesis of a Naturally Derived Protein Kinase Inhibitor that Selectively Inhibits Distinct Classes of Serine/Threonine Kinases.Journal of natural products · 2023Article
- Biochemical Discovery, Intracellular Evaluation, and Crystallographic Characterization of Synthetic and Natural Product Adenosine 3',5'-Cyclic Monophosphate-Dependent Protein Kinase A (PKA) Inhibitors.ACS pharmacology & translational science · 2023Article
- Article
- Activation of PKA via asymmetric allosteric coupling of structurally conserved cyclic nucleotide binding domains.Nature communications · 2019Article
- Two PKA RIα holoenzyme states define ATP as an isoform-specific orthosteric inhibitor that competes with the allosteric activator, cAMP.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Structures of the PKA RIα Holoenzyme with the FLHCC Driver J-PKAcα or Wild-Type PKAcα.Structure (London, England : 1993) · 2019Article
- Switching of the folding-energy landscape governs the allosteric activation of protein kinase A.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Molecular Insights into the Mechanisms of SUN1 Oligomerization in the Nuclear Envelope.Biophysical journal · 2018Article
- Conserved salt-bridge competition triggered by phosphorylation regulates the protein interactome.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Molecular Simulations Reveal an Unresolved Conformation of the Type IA Protein Kinase A Regulatory Subunit and Suggest Its Role in the cAMP Regulatory Mechanism.Biochemistry · 2017Article
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Authors and funding
7 authors.
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Abstract
Close-range electrostatic interactions that form salt bridges are key components of protein stability. Here we investigate the role of these charged interactions in modulating the allosteric activation of protein kinase A (PKA) via computational and experimental mutational studies of a conserved basic patch located in the regulatory subunit's B/C helix. Molecular dynamics simulations evidenced the presence of an extended network of fluctuating salt bridges spanning the helix and connecting the two cAMP binding domains in its extremities. Distinct changes in the flexibility and conformational free energy landscape induced by the separate mutations of Arg239 and Arg241 suggested alteration of cAMP-induced allosteric activation and were verified through in vitro fluorescence polarization assays. These observations suggest a mechanical aspect to the allosteric transition of PKA, with Arg239 and Arg241 acting in competition to promote the transition between the two protein functional states. The simulations also provide a molecular explanation for the essential role of Arg241 in allowing cooperative activation, by evidencing the existence of a stable interdomain salt bridge with Asp267. Our integrated approach points to the role of salt bridges not only in protein stability but also in promoting conformational transition and function.
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