ArticleScientific reports2016
Imatinib binding to human c-Src is coupled to inter-domain allostery and suggests a novel kinase inhibition strategy.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 16 citations in OpenAlex.
- The critical role of the proto-oncogene c-Kit in TSC renal cystogenesis.EMBO molecular medicine · 2026Article
- c-KIT joins the TSC ToolKIT: a new driver of renal cystogenesis.EMBO molecular medicine · 2026Article
- Involvement of Rho-Associated Coiled-Coil Containing Kinase (ROCK) in BCR-ABL1 Tyrosine Kinase Inhibitor Cardiovascular Toxicity.JACC. CardioOncology · 2022Article
- Are off-target effects of imatinib the key to improving beta-cell function in diabetes?Upsala journal of medical sciences · 2022Review
- Regulation of blood-brain barrier integrity by microglia in health and disease: A therapeutic opportunity.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2020Review
- Differential impact of BTK active site inhibitors on the conformational state of full-length BTK.eLife · 2020Article
- Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases.Molecular cell · 2020Article
- Pharmacophore-based virtual screening for the identification of the novel Src inhibitor SJG-136 against lung cancer cell growth and motility.American journal of cancer research · 2020Article
- Demonstration of Binding Induced Structural Plasticity in a SH2 Domain.Frontiers in molecular biosciences · 2020Article
- Survey of solution dynamics in Src kinase reveals allosteric cross talk between the ligand binding and regulatory sites.Nature communications · 2017Article
- Analysis of phosphoinositide 3-kinase inhibitors by bottom-up electron-transfer dissociation hydrogen/deuterium exchange mass spectrometry.The Biochemical journal · 2017Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Imatinib (Gleevec), a non-receptor tyrosine kinase inhibitor (nRTKI), is one of the most successful anti-neoplastic drugs in clinical use. However, imatinib-resistant mutations are increasingly prevalent in patient tissues and driving development of novel imatinib analogs. We present a detailed study of the conformational dynamics, in the presence and absence of bound imatinib, for full-length human c-Src using hydrogen-deuterium exchange and mass spectrometry. Our results demonstrate that imatinib binding to the kinase domain effects dynamics of proline-rich or phosphorylated peptide ligand binding sites in distal c-Src SH3 and SH2 domains. These dynamic changes in functional regulatory sites, distal to the imatinib binding pocket, show similarities to structural transitions involved in kinase activation. These data also identify imatinib-sensitive, and imatinib-resistant, mutation sites. Thus, the current study identifies novel c-Src allosteric sites associated with imatinib binding and kinase activation and provide a framework for follow-on development of TKI binding modulators.
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