ArticleACS chemical biology2019
Targeting Dynamic ATP-Binding Site Features Allows Discrimination between Highly Homologous Protein Kinases.
Article in ACS chemical biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 25 citations in OpenAlex.
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- Advances in pyrazolo[1,5-RSC advances · 2025Review
- Slower CDK4 and faster CDK2 activation in the cell cycle.Structure (London, England : 1993) · 2024Article
- Discovery of a CK2α'-Biased ATP-Competitive Inhibitor from a High-Throughput Screen of an Allosteric-Inhibitor-Like Compound Library.ACS chemical neuroscience · 2024Article
- Profiling of drug resistance in Src kinase at scale uncovers a regulatory network coupling autoinhibition and catalytic domain dynamics.Cell chemical biology · 2024Article
- Identification of CK2α' selective inhibitors by the screening of an allosteric-kinase-inhibitor-like compound library.bioRxiv : the preprint server for biology · 2024Article
- An essentialFrontiers in parasitology · 2023Article
- ATP-site inhibitors induce unique conformations of the acute myeloid leukemia-associated Src-family kinase, Fgr.Structure (London, England : 1993) · 2022Article
- Antioxidant and Anti-Inflammatory Activity ofAntioxidants (Basel, Switzerland) · 2021Article
- Norstictic Acid Is a Selective Allosteric Transcriptional Regulator.Journal of the American Chemical Society · 2021Article
- Druggable Transient Pockets in Protein Kinases.Molecules (Basel, Switzerland) · 2021Review
- Reining in BTK: Interdomain Interactions and Their Importance in the Regulatory Control of BTK.Frontiers in cell and developmental biology · 2021Review
- Article
- Parallel Chemoselective Profiling for Mapping Protein Structure.Cell chemical biology · 2020Article
- How ATP-Competitive Inhibitors Allosterically Modulate Tyrosine Kinases That Contain a Src-like Regulatory Architecture.ACS chemical biology · 2020Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
ATP-competitive inhibitors that demonstrate exquisite selectivity for specific members of the human kinome have been developed. Despite this success, the identification of highly selective inhibitors is still very challenging, and it is often not possible to rationally engineer selectivity between the ATP-binding sites of kinases, especially among closely related family members. Src-family kinases (SFKs) are a highly homologous family of eight multidomain, nonreceptor tyrosine kinases that play general and specialized roles in numerous cellular processes. The high sequence and functional similarities between SFK members make it hard to rationalize how selectivity can be gained with inhibitors that target the ATP-binding site. Here, we describe the development of a series of inhibitors that are highly selective for the ATP-binding sites of the SFKs Lyn and Hck over other SFKs. By biochemically characterizing how these selective ATP-competitive inhibitors allosterically influence the global conformation of SFKs, we demonstrate that they most likely interact with a binding pocket created by the movement of the conformationally flexible helix αC in the ATP-binding site. With a series of sequence swap experiments, we show that sensitivity to this class of selective inhibitors is due to the identity of residues that control the conformational flexibility of helix αC rather than any specific ATP-binding site interactions. Thus, the ATP-binding sites of highly homologous kinases can be discriminated by targeting heterogeneity within conformationally flexible regions.
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Registered trials
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