ArticlePLoS computational biology2014
The SH2 domain regulates c-Abl kinase activation by a cyclin-like mechanism and remodulation of the hinge motion.
Article in PLoS computational biology, 2014. 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, 34 citations in OpenAlex.
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- Lipid Pocket Binders Impose Allosteric Changes of Protein Dynamics Around the Active Site of the Protein Kinase p38α.Angewandte Chemie (International ed. in English) · 2026Article
- Update on Structure and Function of SH2 Domains: Mechanisms and Emerging Targeting Strategies.International journal of molecular sciences · 2025Review
- Activity of STAMP inhibitors inBlood neoplasia · 2025Article
- The structural influence of the oncogenic driver mutation N642H in the STAT5B SH2 domain.Protein science : a publication of the Protein Society · 2025Article
- Article
- Dynamozones are the most obvious sign of the evolution of conformational dynamics in HIV-1 protease.Scientific reports · 2023Article
- Allosteric regulation of autoinhibition and activation of c-Abl.Computational and structural biotechnology journal · 2022Article
- How multisite phosphorylation impacts the conformations of intrinsically disordered proteins.PLoS computational biology · 2021Article
- A Catalytically Disabled Double Mutant of Src Tyrosine Kinase Can Be Stabilized into an Active-Like Conformation.Journal of molecular biology · 2018Article
- Atomic view of the energy landscape in the allosteric regulation of Abl kinase.Nature structural & molecular biology · 2017Article
- Allosteric Communication Networks in Proteins Revealed through Pocket Crosstalk Analysis.ACS central science · 2017Article
- Conformational transition of FGFR kinase activation revealed by site-specific unnatural amino acid reporter and single molecule FRET.Scientific reports · 2017Article
- An Allosteric Cross-Talk Between the Activation Loop and the ATP Binding Site Regulates the Activation of Src Kinase.Scientific reports · 2016Article
- Towards a Molecular Understanding of the Link between Imatinib Resistance and Kinase Conformational Dynamics.PLoS computational biology · 2015Article
- Crystal structure of an SH2-kinase construct of c-Abl and effect of the SH2 domain on kinase activity.The Biochemical journal · 2015Article
Corrections and comments
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Authors and funding
6 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Regulation of the c-Abl (ABL1) tyrosine kinase is important because of its role in cellular signaling, and its relevance in the leukemiogenic counterpart (BCR-ABL). Both auto-inhibition and full activation of c-Abl are regulated by the interaction of the catalytic domain with the Src Homology 2 (SH2) domain. The mechanism by which this interaction enhances catalysis is not known. We combined computational simulations with mutagenesis and functional analysis to find that the SH2 domain conveys both local and global effects on the dynamics of the catalytic domain. Locally, it regulates the flexibility of the αC helix in a fashion reminiscent of cyclins in cyclin-dependent kinases, reorienting catalytically important motifs. At a more global level, SH2 binding redirects the hinge motion of the N and C lobes and changes the conformational equilibrium of the activation loop. The complex network of subtle structural shifts that link the SH2 domain with the activation loop and the active site may be partially conserved with other SH2-domain containing kinases and therefore offer additional parameters for the design of conformation-specific inhibitors.
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