ArticleThe Journal of biological chemistry2013
Enhanced SH3/linker interaction overcomes Abl kinase activation by gatekeeper and myristic acid binding pocket mutations and increases sensitivity to small molecule inhibitors.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 32 citations in OpenAlex.
- Constraining regulatory domain dynamics of the Src kinase Fgr increases ATP-site inhibitor sensitivity and impairs bone marrow engraftment.Cell reports · 2026Article
- Autophosphorylation of oncoprotein TEL-ABL in myeloid and lymphoid cells confers resistance to the allosteric ABL inhibitor asciminib.Science signaling · 2025Article
- Constitutive activation of the Src-family kinases Fgr and Hck enhances the tumor burden of acute myeloid leukemia cells in immunocompromised mice.Scientific reports · 2025Article
- Protein conformational ensembles in function: roles and mechanisms.RSC chemical biology · 2023Review
- Article
- Allosteric regulation of autoinhibition and activation of c-Abl.Computational and structural biotechnology journal · 2022Article
- Synergy and Antagonism between Allosteric and Active-Site Inhibitors of Abl Tyrosine Kinase.Angewandte Chemie (International ed. in English) · 2021Article
- Article
- Selective Inhibition of the Myeloid Src-Family Kinase Fgr Potently Suppresses AML Cell Growth in Vitro and in Vivo.ACS chemical biology · 2018Article
- Single nucleotide editing without DNA cleavage using CRISPR/Cas9-deaminase in the sea urchin embryo.Developmental dynamics : an official publication of the American Association of Anatomists · 2017Article
- Atomic view of the energy landscape in the allosteric regulation of Abl kinase.Nature structural & molecular biology · 2017Article
- Dual inhibition of Fes and Flt3 tyrosine kinases potently inhibits Flt3-ITD+ AML cell growth.PloS one · 2017Article
- Article
- Computational study of the "DFG-flip" conformational transition in c-Abl and c-Src tyrosine kinases.The journal of physical chemistry. B · 2015Article
- Applications of hydrogen/deuterium exchange MS from 2012 to 2014.Analytical chemistry · 2015Review
- Fluorescence Polarization Screening Assays for Small Molecule Allosteric Modulators of ABL Kinase Function.PloS one · 2015Article
- Changes in signal transducer and activator of transcription 3 (STAT3) dynamics induced by complexation with pharmacological inhibitors of Src homology 2 (SH2) domain dimerization.The Journal of biological chemistry · 2014Article
- The SH2 domain regulates c-Abl kinase activation by a cyclin-like mechanism and remodulation of the hinge motion.PLoS computational biology · 2014Article
- Defying c-Abl signaling circuits through small allosteric compounds.Frontiers in genetics · 2014Article
- Differential sensitivity of Src-family kinases to activation by SH3 domain displacement.PloS one · 2014Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Multidomain kinases such as c-Src and c-Abl are regulated by complex allosteric interactions involving their noncatalytic SH3 and SH2 domains. Here we show that enhancing natural allosteric control of kinase activity by SH3/linker engagement has long-range suppressive effects on the kinase activity of the c-Abl core. Surprisingly, enhanced SH3/linker interaction also dramatically sensitized the Bcr-Abl tyrosine kinase associated with chronic myelogenous leukemia to small molecule inhibitors that target either the active site or the myristic acid binding pocket in the kinase domain C-lobe. Dynamics analyses using hydrogen exchange mass spectrometry revealed a remarkable allosteric network linking the SH3 domain, the myristic acid binding pocket, and the active site of the c-Abl core, providing a structural basis for the biological observations. These results suggest a rational strategy for enhanced drug targeting of Bcr-Abl and other multidomain kinase systems that use multiple small molecules to exploit natural mechanisms of kinase control.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.