ArticleBiophysical journal2018
Allosteric KRas4B Can Modulate SOS1 Fast and Slow Ras Activation Cycles.
Article in Biophysical journal, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 38 citations in OpenAlex.
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- In Silico Identification of Putative Allosteric Pockets and Inhibitors for the KRASG13D-SOS1 Complex in Cancer Therapy.International journal of molecular sciences · 2025Article
- Osteoblast-Derived ECM1 Promotes Anti-Androgen Resistance in Bone Metastatic Prostate Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Positive feedback in Ras activation by full-length SOS arises from autoinhibition release mechanism.Biophysical journal · 2024Article
- Tumor-derived RHOA mutants interact with effectors in the GDP-bound state.Nature communications · 2024Article
- Studying early structural changes in SOS1 mediated KRAS activation mechanism.Current research in structural biology · 2024Article
- Higher-order interactions of Bcr-Abl can broaden chronic myeloid leukemia (CML) drug repertoire.Protein science : a publication of the Protein Society · 2023Article
- The Importance of MgChemistry (Weinheim an der Bergstrasse, Germany) · 2022Article
- Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs.Journal of molecular biology · 2022Review
- The structural basis of BCR-ABL recruitment of GRB2 in chronic myelogenous leukemia.Biophysical journal · 2022Article
- 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
- Autopromotion of K-Ras4B Feedback Activation Through an SOS-Mediated Long-Range Allosteric Effect.Frontiers in molecular biosciences · 2022Article
- The structural basis of Akt PH domain interaction with calmodulin.Biophysical journal · 2021Article
- Inhibition of Nonfunctional Ras.Cell chemical biology · 2021Review
- Active and Inactive Cdc42 Differ in Their Insert Region Conformational Dynamics.Biophysical journal · 2021Article
- The mechanism of activation of monomeric B-Raf V600E.Computational and structural biotechnology journal · 2021Article
- Fragment-derived modulators of an industrial β-glucosidase.The Biochemical journal · 2020Article
- SOS1 interacts with Grb2 through regions that induce closed nSH3 conformations.The Journal of chemical physics · 2020Article
- High-Affinity Interactions of the nSH3/cSH3 Domains of Grb2 with the C-Terminal Proline-Rich Domain of SOS1.Journal of the American Chemical Society · 2020Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
Membrane-anchored Ras family proteins are activated by guanine nucleotide exchange factors such as SOS1. The CDC25 domain of SOS1 catalyzes GDP-to-GTP exchange, thereby activating Ras. Here, we aim to decipher the activation mechanism of KRas4B, a significantly mutated oncogene. We perform large-scale molecular dynamics simulations on 12 SOS1 systems, scrutinizing each step in two possible KRas4B activation cycles, fast and slow. To activate KRas4B at the CDC25 catalytic site, the allosteric site in the Ras exchanger motif (REM) domain of SOS1 needs to recruit a (nucleotide-bound) KRas4B molecule. Our simulations indicate that KRas4B-GTP interacts with the REM allosteric site more strongly than with the CDC25 catalytic site, consistent with its allosteric role in the GDP-to-GTP exchange. In the fast cycle, the allosteric KRas4B-GTP induces conformational change at the catalytic site. The conformational change facilitates loading KRas4B-GDP at the catalytic site and opening the KRas4B nucleotide-binding site for GDP release and GTP binding. GTP binding reduces the affinity of KRas4B-GTP to the CDC25 catalytic site, resulting in its release. By contrast, in the slow cycle, KRas4B-GDP binds at the allosteric REM site. The limited, altered conformational change that it induces prevents the exact alignments of switch I and II of KRas4B. The increasing binding strength at both binding sites due to interactions of regions other than switch I and II retards GDP release from the catalytic KRas4B, thus KRas4B activation. The accelerated activation cycle supports a positive feedback loop with allosteric signals communicating between the two Ras molecules and is the predominant, native function of SOS. SOS1 activation details may help drug discovery to inhibit Ras activation.
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