ArticleProceedings of the National Academy of Sciences of the United States of America2018
Water-mediated conformational preselection mechanism in substrate binding cooperativity to protein kinase A.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Computational design of highly signalling-active membrane receptors through solvent-mediated allosteric networks.Nature chemistry · 2025Article
- Entropy driven cooperativity effect in multi-site drug optimization targeting SARS-CoV-2 papain-like protease.Cellular and molecular life sciences : CMLS · 2023Article
- Dynamic equilibria in protein kinases.Current opinion in structural biology · 2021Review
- Osmosensing by WNK Kinases.Molecular biology of the cell · 2021Article
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2 authors.
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Abstract
Substrate binding cooperativity in protein kinase A (PKA) seems to involve allosteric coupling between the two binding sites. It received significant attention, but its molecular basis still remains not entirely clear. Based on long molecular dynamics of PKA and its complexes, we characterized an allosteric pathway that links ATP binding to the redistribution of states adopted by a protein substrate positioning segment in favor of those that warrant correct binding. We demonstrate that the cooperativity mechanism critically depends on the presence of water in two distinct, buried hydration sites. One holds just a single water molecule, which acts as a switchable hydrogen bond bridge along the allosteric pathway. The second, filled with partially disordered solvent, is essential for providing a smooth free energy landscape underlying conformational transitions of the peptide binding region. Our findings remain in agreement with experimental data, also concerning the cooperativity abolishing effect of the Y204A mutation, and indicate a plausible molecular mechanism contributing to experimentally observed binding cooperativity of the two substrates.
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