ArticleBiochemistry2009
A transition path ensemble study reveals a linchpin role for Mg(2+) during rate-limiting ADP release from protein kinase A.
Article in Biochemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 50 citations in OpenAlex.
- 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
- Interaction networks explain holoenzyme allostery in Protein Kinase A.Kinases and phosphatases · 2023Article
- Article
- Edmond Fischer's kinase legacy: History of the protein kinase inhibitor and protein kinase A.IUBMB life · 2023Article
- The "violin model": Looking at community networks for dynamic allostery.The Journal of chemical physics · 2023Review
- Molecular-dynamics simulation methods for macromolecular crystallography.Acta crystallographica. Section D, Structural biology · 2023Article
- Inflammatory macrophages exacerbate neutrophil-driven joint damage through ADP/P2YScience China. Life sciences · 2022Article
- Druggable Transient Pockets in Protein Kinases.Molecules (Basel, Switzerland) · 2021Review
- 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
- Zooming in on protons: Neutron structure of protein kinase A trapped in a product complex.Science advances · 2019Article
- The Molecular Basis for Specificity at the Level of the Protein Kinase a Catalytic Subunit.Frontiers in endocrinology · 2018Review
- Divalent Metal Ions Mg²⁺ and Ca²⁺ Have Distinct Effects on Protein Kinase A Activity and Regulation.ACS chemical biology · 2015Article
- Phosphoryl Transfer Reaction Snapshots in Crystals: INSIGHTS INTO THE MECHANISM OF PROTEIN KINASE A CATALYTIC SUBUNIT.The Journal of biological chemistry · 2015Article
- The energy landscape of adenylate kinase during catalysis.Nature structural & molecular biology · 2015Article
- Molecular features of product release for the PKA catalytic cycle.Biochemistry · 2015Article
- Bridging scales through multiscale modeling: a case study on protein kinase A.Frontiers in physiology · 2015Review
- A QM/MM study of the associative mechanism for the phosphorylation reaction catalyzed by protein kinase A and its D166A mutant.Journal of computer-aided molecular design · 2014Article
- Dynamic architecture of a protein kinase.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Phosphoryl transfer by protein kinase A is captured in a crystal lattice.Journal of the American Chemical Society · 2013Article
- Enzyme cofactors: double-edged sword for catalysis.Nature chemistry · 2013Article
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
Protein kinases are key regulators of diverse signaling networks critical for growth and development. Protein kinase A (PKA) is an important kinase prototype that phosphorylates protein targets at Ser and Thr residues by converting ATP to ADP. Mg(2+) ions play a crucial role in regulating phosphoryl transfer and can limit overall enzyme turnover by affecting ADP release. However, the mechanism by which Mg(2+) participates in ADP release is poorly understood. Here we use a novel transition path ensemble technique, the harmonic Fourier beads method, to explore the atomic and energetic details of the Mg(2+)-dependent ADP binding and release. Our studies demonstrate that adenine-driven ADP binding to PKA creates three ion-binding sites at the ADP/PKA interface that are absent otherwise. Two of these sites bind the previously characterized Mg(2+) ions, whereas the third site binds a monovalent cation with high affinity. This third site can bind the P-3 residue of substrate proteins and may serve as a reporter of the active site occupation. Binding of Mg(2+) ions restricts mobility of the Gly-rich loop that closes over the active site. We find that simultaneous release of ADP with Mg(2+) ions from the active site is unfeasible. Thus, we conclude that Mg(2+) ions act as a linchpin and that at least one ion must be removed prior to pyrophosphate-driven ADP release. The results of the present study enhance understanding of Mg(2+)-dependent association of nucleotides with protein kinases.
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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.