ArticleBiophysical journal2009
Computational modeling of structurally conserved cancer mutations in the RET and MET kinases: the impact on protein structure, dynamics, and stability.
Article in Biophysical journal, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 47 citations in OpenAlex.
- Article
- Computational studies on the functional and structural impact of pathogenic mutations in enzymes.Protein science : a publication of the Protein Society · 2025Review
- RET signaling pathway and RET inhibitors in human cancer.Frontiers in oncology · 2022Review
- Analysis and Interpretation of the Impact of Missense Variants in Cancer.International journal of molecular sciences · 2021Review
- 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
- Mutations in penicillin-binding protein 2 from cephalosporin-resistantThe Journal of biological chemistry · 2020Article
- Computational algorithms for in silico profiling of activating mutations in cancer.Cellular and molecular life sciences : CMLS · 2019Review
- Analysis of somatic mutations across the kinome reveals loss-of-function mutations in multiple cancer types.Scientific reports · 2017Article
- Recent advances in the biology and therapy of medullary thyroid carcinoma.F1000Research · 2017Review
- Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets.Nature communications · 2016Article
- Hereditary breast and ovarian cancer: new genes in confined pathways.Nature reviews. Cancer · 2016Review
- Hotspot mutations in KIT receptor differentially modulate its allosterically coupled conformational dynamics: impact on activation and drug sensitivity.PLoS computational biology · 2014Article
- Oncogenic potential is related to activating effect of cancer single and double somatic mutations in receptor tyrosine kinases.Human mutation · 2012Article
- Predicting folding free energy changes upon single point mutations.Bioinformatics (Oxford, England) · 2012Article
- Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2.Clinics (Sao Paulo, Brazil) · 2012Review
- Analyzing effects of naturally occurring missense mutations.Computational and mathematical methods in medicine · 2012Article
- Annotating individual human genomes.Genomics · 2011Review
- Computational modeling of allosteric communication reveals organizing principles of mutation-induced signaling in ABL and EGFR kinases.PLoS computational biology · 2011Article
- Rapid and accurate ranking of binding affinities of epidermal growth factor receptor sequences with selected lung cancer drugs.Journal of the Royal Society, Interface · 2011Article
- Mutation D816V alters the internal structure and dynamics of c-KIT receptor cytoplasmic region: implications for dimerization and activation mechanisms.PLoS computational biology · 2011Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Structural and biochemical characterization of protein kinases that confer oncogene addiction and harbor a large number of disease-associated mutations, including RET and MET kinases, have provided insights into molecular mechanisms associated with the protein kinase activation in human cancer. In this article, structural modeling, molecular dynamics, and free energy simulations of a structurally conserved mutational hotspot, shared by M918T in RET and M1250T in MET kinases, are undertaken to quantify the molecular mechanism of activation and the functional role of cancer mutations in altering protein kinase structure, dynamics, and stability. The mechanistic basis of the activating RET and MET cancer mutations may be driven by an appreciable free energy destabilization of the inactive kinase state in the mutational forms. According to our results, the locally enhanced mobility of the cancer mutants and a higher conformational entropy are counterbalanced by a larger enthalpy loss and result in the decreased thermodynamic stability. The computed protein stability differences between the wild-type and cancer kinase mutants are consistent with circular dichroism spectroscopy and differential scanning calorimetry experiments. These results support the molecular mechanism of activation, which causes a detrimental imbalance in the dynamic equilibrium shifted toward the active form of the enzyme. Furthermore, computer simulations of the inhibitor binding with the oncogenic and drug-resistant RET mutations have also provided a plausible molecular rationale for the observed differences in the inhibition profiles, which is consistent with the experimental data. Finally, structural mapping of RET and MET cancer mutations and the computed protein stability changes suggest a similar mechanism of activation, whereby the cancer mutations which display the higher oncogenic activity tend to have the greatest destabilization effect on the inactive kinase structure.
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