ArticleComputational and structural biotechnology journal2020
The quaternary assembly of KRas4B with Raf-1 at the membrane.
Article in Computational and structural biotechnology journal, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 66 citations in OpenAlex.
- Allostery in Biomolecular Condensates.Journal of molecular biology · 2026Review
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- Oncogenic PI3Kα variants reveal graded conformational spectrum with mutation-specific cryptic pockets.bioRxiv : the preprint server for biology · 2025Article
- Distinct Allosteric Networks in CDK4 and CDK6 in the Cell Cycle and in Drug Resistance.Journal of molecular biology · 2025Article
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- Slower CDK4 and faster CDK2 activation in the cell cycle.Structure (London, England : 1993) · 2024Article
- K128 ubiquitination constrains RAS activity by expanding its binding interface with GAP proteins.The EMBO journal · 2024Article
- SIRT4 as a novel interactor and candidate suppressor of C-RAF kinase in MAPK signaling.Life science alliance · 2024Article
- CDK2 and CDK4: Cell Cycle Functions Evolve Distinct, Catalysis-Competent Conformations, Offering Drug Targets.JACS Au · 2024Article
- Cancer and Autism: How PTEN Mutations Degrade Function at the Membrane and Isoform Expression in the Human Brain.Journal of molecular biology · 2023Article
- Protein conformational ensembles in function: roles and mechanisms.RSC chemical biology · 2023Review
- Dynamic regulation of RAS and RAS signaling.The Biochemical journal · 2023Article
- Mechanistic Insights into the Protection Effect of Argonaute-RNA Complex on the HCV Genome.Biomolecules · 2022Article
- Exploring CRD mobility during RAS/RAF engagement at the membrane.Biophysical journal · 2022Article
- Pan-KRAS inhibitors suppress proliferation through feedback regulation in pancreatic ductal adenocarcinoma.Acta pharmacologica Sinica · 2022Article
- Computational Dissection of the Role of Trp305 in the Regulation of the Death-Associated Protein Kinase-Calmodulin Interaction.Biomolecules · 2022Article
- Mechanistic Insights into the Mechanism of Inhibitor Selectivity toward the Dark Kinase STK17B against Its High Homology STK17A.Molecules (Basel, Switzerland) · 2022Article
- Mechanism of activation and the rewired network: New drug design concepts.Medicinal research reviews · 2022Review
- Review
- Allosteric regulation of autoinhibition and activation of c-Abl.Computational and structural biotechnology journal · 2022Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
Abstract
Proximally located in the membrane, oncogenic Ras dimers (or nanoclusters) can recruit and promote Raf dimerization and MAPK (Raf/MEK/ERK) signaling. Among Ras isoforms, KRas4B is the most frequently mutated. Recent data on the binary KRas4B-Raf-1 complex suggested that Raf-1 CRD not only executes membrane anchorage, but also supports the high-affinity interaction of Raf-1 RBD with KRas4B catalytic domain. For a detailed mechanistic picture of Raf activation at the membrane, we employ explicit MD simulations of the quaternary KRas4B-Raf-1 complex. The complex contains two active GTP-bound KRas4B proteins forming a dimer through the allosteric lobe interface and two tandem RBD-CRD segments of Raf-1 interacting with the effector lobes at both ends of the KRas4B dimer. We show that Raf-1 RBD-CRD supports stable KRas4B dimer at preferred interface and orientation at the membrane, thereby cooperatively enhancing the affinity of the KRas4B-Raf-1 interaction. We propose that a Ras dimer at the membrane can increase the population of proximal Raf kinase domains, promoting kinase domain dimerization in the cytoplasm. Collectively, the dynamic Ras-Raf assembly promotes Raf activation not by allostery; instead, Ras activates Raf by shifting its ensemble toward kinase domain-accessible states through enhanced affinity at the membrane.
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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.