ArticleProceedings of the National Academy of Sciences of the United States of America2013
Identification of a hidden strain switch provides clues to an ancient structural mechanism in protein kinases.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31 citing papers in PubMed, 50 citations in OpenAlex.
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- Insights into Fluctuations of Structure of Proteins: Significance of Intermediary States in Regulating Biological Functions.Polymers · 2022Review
- Kincore: a web resource for structural classification of protein kinases and their inhibitors.Nucleic acids research · 2022Article
- Evolution of Functional Diversity in the Holozoan Tyrosine Kinome.Molecular biology and evolution · 2021Article
- Hypervariability of accessible and inaccessible conformational space of proteins.Current research in structural biology · 2021Article
- Emerging roles of the αC-β4 loop in protein kinase structure, function, evolution, and disease.IUBMB life · 2020Review
- A Dynamic Switch in Inactive p38γ Leads to an Excited State on the Pathway to an Active Kinase.Biochemistry · 2019Article
- The Novel Serine/Threonine Protein Kinase LmjF.22.0810 fromBiomolecules · 2019Article
- Tracing the origin and evolution of pseudokinases across the tree of life.Science signaling · 2019Article
- Coupled regulation by the juxtamembrane and sterile α motif (SAM) linker is a hallmark of ephrin tyrosine kinase evolution.The Journal of biological chemistry · 2018Article
- Computational and Experimental Characterization of Patient Derived Mutations Reveal an Unusual Mode of Regulatory Spine Assembly and Drug Sensitivity in EGFR Kinase.Biochemistry · 2017Article
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4 authors at 1 institution in 1 country.
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Abstract
The protein kinase catalytic domain contains several conserved residues of unknown functions. Here, using a combination of computational and experimental approaches, we show that the function of some of these residues is to maintain the backbone geometry of the active site in a strained conformation. Specifically, we find that the backbone geometry of the catalytically important HRD motif deviates from ideality in high-resolution structures and the strained geometry results in favorable hydrogen bonds with conserved noncatalytic residues in the active site. In particular, a conserved aspartate in the F-helix hydrogen bonds to the strained HRD backbone in diverse eukaryotic and eukaryotic-like protein kinase crystal structures. Mutations that alter this hydrogen-bonding interaction impair catalytic activity in Aurora kinase. Although the backbone strain is present in most active conformations, several inactive conformations lack the strain because of a peptide flip in the HRD backbone. The peptide flip is correlated with loss of hydrogen bonds with the F-helix aspartate as well as with other interactions associated with kinase regulation. Within protein kinases that are regulated by activation loop phosphorylation, the strained residue is an arginine, which coordinates with the activation loop phosphate. Based on analysis of strain across the protein kinase superfamily, we propose a model in which backbone strain co-evolved with conserved residues for allosteric control of catalytic activity. Our studies provide new clues for the design of allosteric protein kinase inhibitors.
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