ArticleChemical science2019
Ligand discrimination between active and inactive activation loop conformations of Aurora-A kinase is unmodified by phosphorylation.
Article in Chemical science, 2019. 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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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
4 citing papers in PubMed, 13 citations in OpenAlex.
- Activation Loop Plasticity and Active Site Coupling in the MAP Kinase, ERK2.Journal of molecular biology · 2023Article
- Exploring the Conformational Landscape and Stability of Aurora A Using Ion-Mobility Mass Spectrometry and Molecular Modeling.Journal of the American Society for Mass Spectrometry · 2022Article
- Dynamic equilibria in protein kinases.Current opinion in structural biology · 2021Review
- Activation loop dynamics are controlled by conformation-selective inhibitors of ERK2.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 4 countries.
Funding
Abstract
Structure-based drug design is commonly used to guide the development of potent and specific enzyme inhibitors. Many enzymes - such as protein kinases - adopt multiple conformations, and conformational interconversion is expected to impact on the design of small molecule inhibitors. We measured the dynamic equilibrium between DFG-in-like active and DFG-out-like inactive conformations of the activation loop of unphosphorylated Aurora-A alone, in the presence of the activator TPX2, and in the presence of kinase inhibitors. The unphosphorylated kinase had a shorter residence time of the activation loop in the active conformation and a shift in the position of equilibrium towards the inactive conformation compared with phosphorylated kinase for all conditions measured. Ligand binding was associated with a change in the position of conformational equilibrium which was specific to each ligand and independent of the kinase phosphorylation state. As a consequence of this, the ability of a ligand to discriminate between active and inactive activation loop conformations was also independent of phosphorylation. Importantly, we discovered that the presence of multiple enzyme conformations can lead to a plateau in the overall ligand
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Registered trials
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