ArticleAngewandte Chemie (International ed. in English)2016
Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation.
Article in Angewandte Chemie (International ed. in English), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
35 citing papers in PubMed, 46 citations in OpenAlex.
- A structure-based modeling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia.iScience · 2026Article
- Cryo-EM structure and biochemical characterization of a BRAF/CRAF heterodimer: Negative charge in the NtA motif is not required for RAF activation.bioRxiv : the preprint server for biology · 2026Article
- Cryo-EM structures of CRAF/MEK1/14-3-3 complexes in autoinhibited and open-monomer states reveal features of RAF regulation.Nature communications · 2025Article
- In-cell single-molecule FRET measurement of cytosolic RAF proteins to investigate the structural states and kinetics among them.Frontiers in molecular biosciences · 2025Article
- Novel RAF-directed approaches to overcome current clinical limits and block the RAS/RAF node.Molecular oncology · 2024Review
- Targeting RAF dimers in RAS mutant tumors: From biology to clinic.Acta pharmaceutica Sinica. B · 2024Review
- Kinetics of diffusion-influenced multisite phosphorylation with enzyme reactivation.Biopolymers · 2024Article
- Targeting CRAF kinase in anti-cancer therapy: progress and opportunities.Molecular cancer · 2023Review
- Investigating the Unbinding of Muscarinic Antagonists from the Muscarinic 3 Receptor.Journal of chemical theory and computation · 2023Article
- A Combination of Conformation-Specific RAF Inhibitors Overcome Drug Resistance Brought about by RAF Overexpression.Biomolecules · 2023Article
- RAS-independent ERK activation by constitutively active KSR3 in non-chordate metazoa.Nature communications · 2023Article
- Targeting KRAS in Pancreatic Cancer.Journal of personalized medicine · 2022Review
- Proteasomal down-regulation of the proapoptotic MST2 pathway contributes to BRAF inhibitor resistance in melanoma.Life science alliance · 2022Article
- The mechanism of Raf activation through dimerization.Chemical science · 2021Article
- Ras isoform-specific expression, chromatin accessibility, and signaling.Biophysical reviews · 2021Review
- A regulatory role of membrane by direct modulation of the catalytic kinase domain.Small GTPases · 2021Review
- PI3K Driver Mutations: A Biophysical Membrane-Centric Perspective.Cancer research · 2021Review
- Emerging RAS-directed therapies for cancer.Cancer drug resistance (Alhambra, Calif.) · 2021Review
- Review
- The Mystery of Rap1 Suppression of Oncogenic Ras.Trends in cancer · 2020Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 4 countries.
Funding
Abstract
RAF kinases are key players in the MAPK signaling pathway and are important targets for personalized cancer therapy. RAF dimerization is part of the physiological activation mechanism, together with phosphorylation, and is known to convey resistance to RAF inhibitors. Herein, molecular dynamics simulations are used to show that phosphorylation of a key N-terminal acidic (NtA) motif facilitates RAF dimerization by introducing several interprotomer salt bridges between the αC-helix and charged residues upstream of the NtA motif. Additionally, we show that the R-spine of RAF interacts with a conserved Trp residue in the vicinity of the NtA motif, connecting the active sites of two protomers and thereby modulating the cooperative interactions in the RAF dimer. Our findings provide a first structure-based mechanism for the auto-transactivation of RAF and could be generally applicable to other kinases, opening new pathways for overcoming dimerization-related drug resistance.
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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.