ArticleThe journal of physical chemistry. B2016
Comparison of the Conformations of KRAS Isoforms, K-Ras4A and K-Ras4B, Points to Similarities and Significant Differences.
Article in The journal of physical chemistry. B, 2016. 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, 55 citations in OpenAlex.
- G12 mutations rewire allosteric communication at the Ras-RalGDS interface.Biophysical journal · 2026Article
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- Structural Dynamics of Rho GTPases.Journal of molecular biology · 2025Review
- In Silico Prediction of New Inhibitors for Kirsten Rat Sarcoma G12D Cancer Drug Target Using Machine Learning-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulation Approaches.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Comparative analysis of KRAS4a and KRAS4b splice variants reveals distinctive structural and functional properties.Science advances · 2024Article
- Conformations and binding pockets of HRas and its guanine nucleotide exchange factors complexes in the guanosine triphosphate exchange process.Journal of computational chemistry · 2022Article
- The mechanism of activation of MEK1 by B-Raf and KSR1.Cellular and molecular life sciences : CMLS · 2022Article
- Identification of functional substates of KRas during GTP hydrolysis with enhanced sampling simulations.Physical chemistry chemical physics : PCCP · 2022Article
- The complex, dynamic SpliceOme of the small GTPase transcripts altered by technique, sex, genetics, tissue specificity, and RNA base editing.Frontiers in cell and developmental biology · 2022Article
- Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies.Biological research · 2021Review
- Ras isoform-specific expression, chromatin accessibility, and signaling.Biophysical reviews · 2021Review
- The structural basis of Akt PH domain interaction with calmodulin.Biophysical journal · 2021Article
- Unveiling the Dynamics of KRAS4b on Lipid Model Membranes.The Journal of membrane biology · 2021Article
- Active and Inactive Cdc42 Differ in Their Insert Region Conformational Dynamics.Biophysical journal · 2021Article
- K-RAS4A: Lead or Supporting Role in Cancer Biology?Frontiers in molecular biosciences · 2021Review
- The mechanism of activation of monomeric B-Raf V600E.Computational and structural biotechnology journal · 2021Article
- Structural impact of GTP binding on downstream KRAS signaling.Chemical science · 2020Article
- The quaternary assembly of KRas4B with Raf-1 at the membrane.Computational and structural biotechnology journal · 2020Article
- The current understanding of KRAS protein structure and dynamics.Computational and structural biotechnology journal · 2020Review
- Calmodulin (CaM) Activates PI3Kα by Targeting the "Soft" CaM-Binding Motifs in Both the nSH2 and cSH2 Domains of p85α.The journal of physical chemistry. B · 2018Article
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3 authors at 3 institutions in 2 countries.
Funding
Abstract
Human HRAS, KRAS, and NRAS genes encode four isoforms of Ras, a p21 GTPase. Mutations in KRAS account for the majority of RAS-driven cancers. The KRAS has two splice variants, K-Ras4A and K-Ras4B. Due to their reversible palmitoylation, K-Ras4A and N-Ras have bimodal signaling states. K-Ras4A and K-Ras4B differ in four catalytic domain residues (G151R/D153E/K165Q/H166Y) and in their disordered C-terminal hypervariable region (HVR). In K-Ras4A, the HVR is not as strongly positively charged as in K-Ras4B (+6e vs +9e). Here, we performed all-atom molecular dynamics simulations to elucidate isoform-specific differences between the two splice variants. We observe that the catalytic domain of GDP-bound K-Ras4A has a more exposed nucleotide binding pocket than K-Ras4B, and the dynamic fluctuations in switch I and II regions also differ; both factors may influence guanine-nucleotide exchange. We further observe that like K-Kas4B, full-length K-Ras4A exhibits nucleotide-dependent HVR fluctuations; however, these fluctuations differ between the GDP-bound forms of K-Ras4A and K-Ras4B. Unlike K-Ras4B where the HVR tends to cover the effector binding region, in K-Ras4A, autoinhibited states are unstable. With lesser charge, the K-Ras4A HVR collapses on itself, making it less available for binding the catalytic domain. Since the HVRs of N- and H-Ras are weakly charged (+1e and +2e, respectively), autoinhibition may be a unique feature of K-Ras4B.
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