ArticleScientific reports2016
The Structural Basis of Oncogenic Mutations G12, G13 and Q61 in Small GTPase K-Ras4B.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 120 papers.
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120 citing papers in PubMed, 214 citations in OpenAlex.
- Targeting molecular and genetic pathways driving tumorigenesis for precision therapy in colorectal cancer.Cancer biology & therapy · 2026Review
- G12 mutations rewire allosteric communication at the Ras-RalGDS interface.Biophysical journal · 2026Article
- Monovalent Nondegrading Molecular Glues: An Updated Overview of Emerging Mechanisms and Therapeutic Development.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Selenium Nanoparticles Selectively Target KRAS G13D to Inhibit Colorectal Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Characterization of KRASNature communications · 2026Article
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- Assessing the Performance of BioEmu in Understanding Protein Dynamics.International journal of molecular sciences · 2026Article
- ELOVL6 activity attenuation induces mutant KRAS degradation.Nature chemical biology · 2026Article
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- Oncogenic driver mutations underlie the spatial tumour immune landscape of non-small cell lung cancer.Nature communications · 2025Article
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- Evaluating the Effect ofJCO precision oncology · 2025Article
- Exploring binding and allosteric energy landscapes for the KRAS interactions with effector proteins using Markov state modeling of conformational ensembles and allosteric network modeling.Protein science : a publication of the Protein Society · 2025Review
- Investigation of potential KRASG12D inhibitors: a comparative study between MRTX1133 and natural compounds via computational structural biology approaches.BMC research notes · 2025Article
- Differential Response and Resistance to KRAS-Targeted Therapy.Molecular carcinogenesis · 2025Review
- Tumour-agnostic kinase inhibitors.Nature reviews. Drug discovery · 2025Review
- Small-Molecule KRAS Inhibitors by Tyrosine Covalent Bond Formation.ChemMedChem · 2025Article
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- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
60 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 4 institutions in 3 countries.
Funding
Abstract
Ras mediates cell proliferation, survival and differentiation. Mutations in K-Ras4B are predominant at residues G12, G13 and Q61. Even though all impair GAP-assisted GTP → GDP hydrolysis, the mutation frequencies of K-Ras4B in human cancers vary. Here we aim to figure out their mechanisms and differential oncogenicity. In total, we performed 6.4 μs molecular dynamics simulations on the wild-type K-Ras4B (K-Ras4B(WT)-GTP/GDP) catalytic domain, the K-Ras4B(WT)-GTP-GAP complex, and the mutants (K-Ras4B(G12C/G12D/G12V)-GTP/GDP, K-Ras4B(G13D)-GTP/GDP, K-Ras4B(Q61H)-GTP/GDP) and their complexes with GAP. In addition, we simulated 'exchanged' nucleotide states. These comprehensive simulations reveal that in solution K-Ras4B(WT)-GTP exists in two, active and inactive, conformations. Oncogenic mutations differentially elicit an inactive-to-active conformational transition in K-Ras4B-GTP; in K-Ras4B(G12C/G12D)-GDP they expose the bound nucleotide which facilitates the GDP-to-GTP exchange. These mechanisms may help elucidate the differential mutational statistics in K-Ras4B-driven cancers. Exchanged nucleotide simulations reveal that the conformational transition is more accessible in the GTP-to-GDP than in the GDP-to-GTP exchange. Importantly, GAP not only donates its R789 arginine finger, but stabilizes the catalytically-competent conformation and pre-organizes catalytic residue Q61; mutations disturb the R789/Q61 organization, impairing GAP-mediated GTP hydrolysis. Together, our simulations help provide a mechanistic explanation of key mutational events in one of the most oncogenic proteins in cancer.
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