ArticlePLoS computational biology2015
Towards a Molecular Understanding of the Link between Imatinib Resistance and Kinase Conformational Dynamics.
Article in PLoS computational biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 69 citations in OpenAlex.
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- Identification of Protein Cryptic Sites via Conformational Dynamics Capturing and Water-Based Pocket Characterization in Molecular Dynamics Simulations.Journal of chemical theory and computation · 2025Article
- Path-Based Nonequilibrium Binding Free Energy Estimation, from Protein-Ligand to RNA-Ligand Binding.Journal of chemical information and modeling · 2025Article
- The FLT3American journal of hematology · 2023Article
- Unraveling Extremely DamagingJournal of personalized medicine · 2023Article
- Evolutionary divergence in the conformational landscapes of tyrosine vs serine/threonine kinases.eLife · 2022Article
- Validation of an Allosteric Binding Site of Src Kinase Identified by Unbiased Ligand Binding Simulations.Journal of molecular biology · 2022Article
- Evaluation of residue variability in a conformation-specific context and during evolutionary sequence reconstruction narrows drug resistance selection in Abl1 tyrosine kinase.Protein science : a publication of the Protein Society · 2022Article
- Activation of Abl1 Kinase Explored Using Well-Tempered Metadynamics Simulations on an Essential Dynamics Sampled Path.Journal of chemical theory and computation · 2021Article
- TYROSINE KINASES: COMPLEX MOLECULAR SYSTEMS CHALLENGING COMPUTATIONAL METHODOLOGIES.The European physical journal. B · 2021Article
- Computer Simulations of the Dissociation Mechanism of Gleevec from Abl Kinase with Milestoning.The journal of physical chemistry. B · 2021Article
- Loop Dynamics and Enzyme Catalysis in Protein Tyrosine Phosphatases.Journal of the American Chemical Society · 2021Article
- TRK xDFG Mutations Trigger a Sensitivity Switch from Type I to II Kinase Inhibitors.Cancer discovery · 2021Article
- Diversity of Long-Lived Intermediates along the Binding Pathway of Imatinib to Abl Kinase Revealed by MD Simulations.Journal of chemical theory and computation · 2020Article
- Cumulative mechanism of several major imatinib-resistant mutations in Abl kinase.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Combining Machine Learning and Enhanced Sampling Techniques for Efficient and Accurate Calculation of Absolute Binding Free Energies.Journal of chemical theory and computation · 2020Article
- Enhanced Molecular Dynamics Simulations of Intrinsically Disordered Proteins.Methods in molecular biology (Clifton, N.J.) · 2020Article
- Dynamics-function relationship in the catalytic domains of N-terminal acetyltransferases.Computational and structural biotechnology journal · 2020Article
- Identification of tyrosine kinase inhibitors that halt Plasmodium falciparum parasitemia.PloS one · 2020Article
- Interleukin-1β drives NEDD8 nuclear-to-cytoplasmic translocation, fostering parkin activation via NEDD8 binding to the P-ubiquitin activating site.Journal of neuroinflammation · 2019Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Due to its inhibition of the Abl kinase domain in the BCR-ABL fusion protein, imatinib is strikingly effective in the initial stage of chronic myeloid leukemia with more than 90% of the patients showing complete remission. However, as in the case of most targeted anti-cancer therapies, the emergence of drug resistance is a serious concern. Several drug-resistant mutations affecting the catalytic domain of Abl and other tyrosine kinases are now known. But, despite their importance and the adverse effect that they have on the prognosis of the cancer patients harboring them, the molecular mechanism of these mutations is still debated. Here by using long molecular dynamics simulations and large-scale free energy calculations complemented by in vitro mutagenesis and microcalorimetry experiments, we model the effect of several widespread drug-resistant mutations of Abl. By comparing the conformational free energy landscape of the mutants with those of the wild-type tyrosine kinases we clarify their mode of action. It involves significant and complex changes in the inactive-to-active dynamics and entropy/enthalpy balance of two functional elements: the activation-loop and the conserved DFG motif. What is more the T315I gatekeeper mutant has a significant impact on the binding mechanism itself and on the binding kinetics.
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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.