ArticleChemical science2020
Structural impact of GTP binding on downstream KRAS signaling.
Article in Chemical science, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 49 citations in OpenAlex.
- Computational identification and characterization of high-risk human KRAS nsSNPs: Impacting structure, ligand binding, and cancer prognosis.Journal, genetic engineering & biotechnology · 2026Article
- GDP-Loaded K-Ras Transiently Binds to Effector B-Raf RBD, Mirroring the Structure of the Active GTP-Loaded Complex.Journal of the American Chemical Society · 2026Article
- Crosstalk between KRAS and miRNAs in pancreatic cancer: Opportunities for its diagnosis, prognosis and therapeutic intervention (Review).International journal of oncology · 2026Review
- Improving Protein Structure Determination by Integrating Ensemble-Driven Molecular Dynamics with Chemical Shift-Based Restraints.Journal of chemical information and modeling · 2026Article
- Article
- Functional Analysis of Rare RAS Variants of Unknown Significance.Cancer research communications · 2025Article
- Site-directed antibodies targeting driver mutations of the KRAS protein.New biotechnology · 2025Article
- Review
- NMRBiomolecular NMR assignments · 2025Article
- Pancreatic Cancer: Pathogenesis and Clinical Studies.MedComm · 2025Review
- KRAS-SOS-1 Inhibition as New Pharmacological Target to Counteract Anaplastic Thyroid Carcinoma (ATC).International journal of molecular sciences · 2025Article
- Deciphering allosteric mechanisms in KRAS activation: insights from GTP-induced conformational dynamics and interaction network reorganization.RSC advances · 2025Article
- Conserved allosteric perturbation of the GTPase domains by region 1 of Ras hypervariable regions.Biophysical journal · 2024Article
- Far-reaching effects of tyrosine64 phosphorylation on Ras revealed with BeFCommunications chemistry · 2024Article
- Bioinformatics and Experimental Validation for Identifying Biomarkers Associated with AMG510 (Sotorasib) Resistance in KRASInternational journal of molecular sciences · 2024Article
- Photonanozyme-Kras-ribosome combination treatment of non-small cell lung cancer after COVID-19.Frontiers in immunology · 2024Review
- Structural insights into the complex of oncogenic KRas4BLife science alliance · 2024Article
- Excited-state observation of active K-Ras reveals differential structural dynamics of wild-type versus oncogenic G12D and G12C mutants.Nature structural & molecular biology · 2023Article
- Mechanism-Based Redesign of GAP to Activate Oncogenic Ras.Journal of the American Chemical Society · 2023Article
- NMR-Chemical-Shift-Driven Protocol Reveals the Cofactor-Bound, Complete Structure of Dynamic Intermediates of the Catalytic Cycle of Oncogenic KRAS G12C Protein and the Significance of the MgInternational journal of molecular sciences · 2023Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Oncogenic RAS proteins, involved in ∼30% of human tumors, are molecular switches of various signal transduction pathways. Here we apply a new protocol for the NMR study of KRAS in its (inactive) GDP- and (activated) GTP-bound form, allowing a comprehensive analysis of the backbone dynamics of its WT-, G12C- and G12D variants. We found that Tyr32 shows opposite mobility with respect to the backbone of its surroundings: it is more flexible in the GDP-bound form while more rigid in GTP-complexes (especially in WT- and G12D-GTP). Using the G12C/Y32F double mutant, we showed that the presence of the hydroxyl group of Tyr32 has a marked effect on the G12C-KRAS-GTP system as well. Molecular dynamics simulations indicate that Tyr32 is linked to the γ-phosphate of GTP in the activated states - an arrangement shown, using QM/MM calculations, to support catalysis. Anchoring Tyr32 to the γ-phosphate contributes to the capture of the catalytic waters participating in the intrinsic hydrolysis of GTP and supports a simultaneous triple proton transfer step (catalytic water → assisting water → Tyr32 → O1G of the γ-phosphate) leading to straightforward product formation. The coupled flip of negatively charged residues of switch I toward the inside of the effector binding pocket potentiates ligand recognition, while positioning of Thr35 to enter the coordination sphere of the Mg
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Registered trials
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.