ArticleThe journal of physical chemistry. B2017
The Activation of c-Src Tyrosine Kinase: Conformational Transition Pathway and Free Energy Landscape.
Article in The journal of physical chemistry. B, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed.
- Defining the Active Conformation of Typical Protein Kinase Domains from Substrate-Bound PDB Structures Enables Active-State AlphaFold2 Models for All 437 Human Catalytic Protein Kinases.bioRxiv : the preprint server for biology · 2026Article
- Unsupervised synchronization of molecular dynamics trajectories via graph embedding and time warping.Bioinformatics (Oxford, England) · 2026Article
- The path forward for protein footprinting, covalent labeling, and mass spectrometry-based protein conformational analyses.Journal of mass spectrometry : JMS · 2024Review
- Recent Developments in the Role of Protein Tyrosine Phosphatase 1B (PTP1B) as a Regulator of Immune Cell Signalling in Health and Disease.International journal of molecular sciences · 2024Review
- Data-driven classification of ligand unbinding pathways.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- TCR Pathway Mutations in Mature T Cell Lymphomas.Journal of immunology (Baltimore, Md. : 1950) · 2023Review
- Phosphorylation of tyrosine 90 in SH3 domain is a new regulatory switch controlling Src kinase.eLife · 2023Article
- Review
- Allostery, and how to define and measure signal transduction.Biophysical chemistry · 2022Review
- A Companion Guide to the String Method with Swarms of Trajectories: Characterization, Performance, and Pitfalls.Journal of chemical theory and computation · 2022Article
- Mechanical force can enhance c-Src kinase activity by impairing autoinhibition.Biophysical journal · 2022Article
- Allosteric regulation of autoinhibition and activation of c-Abl.Computational and structural biotechnology journal · 2022Article
- Mechanistic Insights Into Co-Administration of Allosteric and Orthosteric Drugs to Overcome Drug-Resistance in T315I BCR-ABL1.Frontiers in pharmacology · 2022Article
- TYROSINE KINASES: COMPLEX MOLECULAR SYSTEMS CHALLENGING COMPUTATIONAL METHODOLOGIES.The European physical journal. B · 2021Article
- String Method with Swarms-of-Trajectories, Mean Drifts, Lag Time, and Committor.The journal of physical chemistry. A · 2021Article
- All-atom adaptively biased path optimization of Src kinase conformational inactivation: Switched electrostatic network in the concerted motion of αC helix and the activation loop.The Journal of chemical physics · 2020Article
- Glycine substitution in SH3-SH2 connector of Hck tyrosine kinase causes population shift from assembled to disassembled state.Biochimica et biophysica acta. General subjects · 2020Article
- Identification of Druggable Kinase Target Conformations Using Markov Model Metastable States Analysis of apo-Abl.Journal of chemical theory and computation · 2020Article
- Allosteric Regulation at the Crossroads of New Technologies: Multiscale Modeling, Networks, and Machine Learning.Frontiers in molecular biosciences · 2020Review
- Autophosphorylation activates c-Src kinase through global structural rearrangements.The Journal of biological chemistry · 2019Article
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Authors and funding
3 authors.
Funding
Abstract
Tyrosine kinases are important cellular signaling allosteric enzymes that regulate cell growth, proliferation, metabolism, differentiation, and migration. Their activity must be tightly controlled, and malfunction can lead to a variety of diseases, particularly cancer. The nonreceptor tyrosine kinase c-Src, a prototypical model system and a representative member of the Src-family, functions as complex multidomain allosteric molecular switches comprising SH2 and SH3 domains modulating the activity of the catalytic domain. The broad picture of self-inhibition of c-Src via the SH2 and SH3 regulatory domains is well characterized from a structural point of view, but a detailed molecular mechanism understanding is nonetheless still lacking. Here, we use advanced computational methods based on all-atom molecular dynamics simulations with explicit solvent to advance our understanding of kinase activation. To elucidate the mechanism of regulation and self-inhibition, we have computed the pathway and the free energy landscapes for the "inactive-to-active" conformational transition of c-Src for different configurations of the SH2 and SH3 domains. Using the isolated c-Src catalytic domain as a baseline for comparison, it is observed that the SH2 and SH3 domains, depending upon their bound orientation, promote either the inactive or active state of the catalytic domain. The regulatory structural information from the SH2-SH3 tandem is allosterically transmitted via the N-terminal linker of the catalytic domain. Analysis of the conformational transition pathways also illustrates the importance of the conserved tryptophan 260 in activating c-Src, and reveals a series of concerted events during the activation process.
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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.