ArticlePLoS computational biology2008
Src kinase conformational activation: thermodynamics, pathways, and mechanisms.
Article in PLoS computational biology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed.
- A Fast Method to Monitor Tyrosine Kinase Inhibitor Mechanisms.Journal of medicinal chemistry · 2024Article
- Chemoprotective effect of baicalin against cyclophosphamide induced ovarian toxicity in mice via inhibition of TGF-β.Heliyon · 2023Article
- TYROSINE KINASES: COMPLEX MOLECULAR SYSTEMS CHALLENGING COMPUTATIONAL METHODOLOGIES.The European physical journal. B · 2021Article
- Markov State Models to Study the Functional Dynamics of Proteins in the Wake of Machine Learning.JACS Au · 2021Review
- Unsupervised Learning Methods for Molecular Simulation Data.Chemical reviews · 2021Article
- Computational studies of anaplastic lymphoma kinase mutations reveal common mechanisms of oncogenic activation.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- 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
- Article
- 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
- Computational algorithms for in silico profiling of activating mutations in cancer.Cellular and molecular life sciences : CMLS · 2019Review
- Towards simple kinetic models of functional dynamics for a kinase subfamily.Nature chemistry · 2018Article
- New insights into the structural dynamics of the kinase JNK3.Scientific reports · 2018Article
- Millisecond dynamics of BTK reveal kinome-wide conformational plasticity within the apo kinase domain.Scientific reports · 2017Article
- Implications of short time scale dynamics on long time processes.Structural dynamics (Melville, N.Y.) · 2017Review
- Tyrosine Kinase Activation and Conformational Flexibility: Lessons from Src-Family Tyrosine Kinases.Accounts of chemical research · 2017Article
- The Activation of c-Src Tyrosine Kinase: Conformational Transition Pathway and Free Energy Landscape.The journal of physical chemistry. B · 2017Article
- Conformational Selection and Induced Fit Mechanisms in the Binding of an Anticancer Drug to the c-Src Kinase.Scientific reports · 2016Article
- Computational study of the W260A activating mutant of Src tyrosine kinase.Protein science : a publication of the Protein Society · 2016Article
- Computational study of the "DFG-flip" conformational transition in c-Abl and c-Src tyrosine kinases.The journal of physical chemistry. B · 2015Article
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Authors and funding
2 authors.
Funding
Abstract
Tyrosine kinases of the Src-family are large allosteric enzymes that play a key role in cellular signaling. Conversion of the kinase from an inactive to an active state is accompanied by substantial structural changes. Here, we construct a coarse-grained model of the catalytic domain incorporating experimental structures for the two stable states, and simulate the dynamics of conformational transitions in kinase activation. We explore the transition energy landscapes by constructing a structural network among clusters of conformations from the simulations. From the structural network, two major ensembles of pathways for the activation are identified. In the first transition pathway, we find a coordinated switching mechanism of interactions among the alphaC helix, the activation-loop, and the beta strands in the N-lobe of the catalytic domain. In a second pathway, the conformational change is coupled to a partial unfolding of the N-lobe region of the catalytic domain. We also characterize the switching mechanism for the alphaC helix and the activation-loop in detail. Finally, we test the performance of a Markov model and its ability to account for the structural kinetics in the context of Src conformational changes. Taken together, these results provide a broad framework for understanding the main features of the conformational transition taking place upon Src activation.
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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.