ArticleProceedings of the National Academy of Sciences of the United States of America2013
Two-state dynamics of the SH3-SH2 tandem of Abl kinase and the allosteric role of the N-cap.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 39 citations in OpenAlex.
- MDPath: Unraveling Allosteric Communication Paths of Drug Targets through Molecular Dynamics Simulations.Journal of chemical information and modeling · 2025Article
- Role of c-ABL in DENV-2 Infection and Actin Remodeling in Vero Cells.International journal of molecular sciences · 2025Article
- Conformational free-energy landscapes of a NaProceedings of the National Academy of Sciences of the United States of America · 2024Article
- SH2 Domains: Folding, Binding and Therapeutical Approaches.International journal of molecular sciences · 2022Review
- Allosteric regulation of autoinhibition and activation of c-Abl.Computational and structural biotechnology journal · 2022Article
- Substrate Specificity of Chimeric Enzymes Formed by Interchange of the Catalytic and Specificity Domains of the 5Molecules (Basel, Switzerland) · 2021Article
- A Novel ELISA-Based Peptide Biosensor Assay for Screening ABL1 ActivityFrontiers in pharmacology · 2021Article
- New Heteroleptic Ruthenium(II) Complexes with Sulfamethoxypyridazine and Diimines as Potential Antitumor Agents.Molecules (Basel, Switzerland) · 2019Article
- Role of c-Abl and nephrin in podocyte cytoskeletal remodeling induced by angiotensin II.Cell death & disease · 2018Article
- Atomic view of the energy landscape in the allosteric regulation of Abl kinase.Nature structural & molecular biology · 2017Article
- Paralog-Specific Patterns of Structural Disorder and Phosphorylation in the Vertebrate SH3-SH2-Tyrosine Kinase Protein Family.Genome biology and evolution · 2016Article
- Mechanism of extracellular ion exchange and binding-site occlusion in a sodium/calcium exchanger.Nature structural & molecular biology · 2016Article
- Angiotensin II down-regulates nephrin-Akt signaling and induces podocyte injury: roleof c-Abl.Molecular biology of the cell · 2016Article
- Regions outside of conserved PxxPxR motifs drive the high affinity interaction of GRB2 with SH3 domain ligands.Biochimica et biophysica acta · 2015Article
- P-loop conformation governed crizotinib resistance in G2032R-mutated ROS1 tyrosine kinase: clues from free energy landscape.PLoS computational biology · 2014Article
- Channeling your inner energy.Nature structural & molecular biology · 2014Article
- Defying c-Abl signaling circuits through small allosteric compounds.Frontiers in genetics · 2014Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The regulation and localization of signaling enzymes is often mediated by accessory modular domains, which frequently function in tandems. The ability of these tandems to adopt multiple conformations is as important for proper regulation as the individual domain specificity. A paradigmatic example is Abl, a ubiquitous tyrosine kinase of significant pharmacological interest. SH3 and SH2 domains inhibit Abl by assembling onto the catalytic domain, allosterically clamping it in an inactive state. We investigate the dynamics of this SH3-SH2 tandem, using microsecond all-atom simulations and differential scanning calorimetry. Our results indicate that the Abl tandem is a two-state switch, alternating between the conformation observed in the structure of the autoinhibited enzyme and another configuration that is consistent with existing scattering data for an activated form. Intriguingly, we find that the latter is the most probable when the tandem is disengaged from the catalytic domain. Nevertheless, an amino acid stretch preceding the SH3 domain, the so-called N-cap, reshapes the free-energy landscape of the tandem and favors the interaction of this domain with the SH2-kinase linker, an intermediate step necessary for assembly of the autoinhibited complex. This allosteric effect arises from interactions between N-cap and the SH2 domain and SH3-SH2 connector, which involve a phosphorylation site. We also show that the SH3-SH2 connector plays a determinant role in the assembly equilibrium of Abl, because mutations thereof hinder the engagement of the SH2-kinase linker. These results provide a thermodynamic rationale for the involvement of N-cap and SH3-SH2 connector in Abl regulation and expand our understanding of the principles of modular domain organization.
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