ArticleProceedings of the National Academy of Sciences of the United States of America2006
A Ras-induced conformational switch in the Ras activator Son of sevenless.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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Who cites it
86 citing papers in PubMed.
- Article
- PTEN Oxidation Promotes Constitutive PI3K Signaling and Inducible Macropinocytosis in Pancreatic Cancer.Cancer research · 2026Article
- Disrupting the KRAS-SOS1 protein-protein interaction: mechanistic rationale for pan-KRAS pathway suppression and combination therapy.Frontiers in chemistry · 2026Review
- Systematic Evaluation of GAPs and GEFs Identifies a Targetable Dependency for Hematopoietic Malignancies.Cancer discovery · 2025Article
- Cryo-EM structure of phospholipase Cε defines N-terminal domains and their roles in activity.Communications biology · 2025Article
- RAS Pathway Inhibitors Combined with Targeted Agents Are Active in Patient-Derived Spheroids with Oncogenic KRAS Variants from Multiple Cancer Types.Cancer research communications · 2025Article
- Genetic and oncogenic features of RASGRF fusions.NPJ precision oncology · 2025Article
- Molecular insights into immune evasion and therapeutic paradigms in pancreatic cancer.Chinese journal of cancer research = Chung-kuo yen cheng yen chiu · 2025Article
- Positive feedback in Ras activation by full-length SOS arises from autoinhibition release mechanism.Biophysical journal · 2024Article
- Allosteric nanobodies to study the interactions between SOS1 and RAS.Nature communications · 2024Article
- Targeting KRASG12D mutation in non-small cell lung cancer: molecular mechanisms and therapeutic potential.Cancer gene therapy · 2024Review
- Bimodality in Ras signaling originates from processivity of the Ras activator SOS without deterministic bistability.Science advances · 2024Article
- Lead Identification of Novel Naphthyridine Derivatives as Potent SOS1 Inhibitors.ACS medicinal chemistry letters · 2024Article
- SOS2 modulates the threshold of EGFR signaling to regulate osimertinib efficacy and resistance in lung adenocarcinoma.Molecular oncology · 2024Article
- Studying early structural changes in SOS1 mediated KRAS activation mechanism.Current research in structural biology · 2024Article
- Review
- Pathogen-specific structural features ofmBio · 2023Article
- RAS and Other Molecular Targets in Pancreatic Cancer: The Next Wave Is Coming.Current treatment options in oncology · 2023Review
- Membranes prime the RapGEF EPAC1 to transduce cAMP signaling.Nature communications · 2023Article
- Translational relevance of SOS1 targeting for KRAS-mutant colorectal cancer.Molecular carcinogenesis · 2023Article
26 more citing papers are in PubMed but not listed here.
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7 authors.
Funding
Abstract
The Ras-specific guanine nucleotide-exchange factors Son of sevenless (Sos) and Ras guanine nucleotide-releasing factor 1 (RasGRF1) transduce extracellular stimuli into Ras activation by catalyzing the exchange of Ras-bound GDP for GTP. A truncated form of RasGRF1 containing only the core catalytic Cdc25 domain is sufficient for stimulating Ras nucleotide exchange, whereas the isolated Cdc25 domain of Sos is inactive. At a site distal to the catalytic site, nucleotide-bound Ras binds to Sos, making contacts with the Cdc25 domain and with a Ras exchanger motif (Rem) domain. This allosteric Ras binding stimulates nucleotide exchange by Sos, but the mechanism by which this stimulation occurs has not been defined. We present a crystal structure of the Rem and Cdc25 domains of Sos determined at 2.0-A resolution in the absence of Ras. Differences between this structure and that of Sos bound to two Ras molecules show that allosteric activation of Sos by Ras occurs through a rotation of the Rem domain that is coupled to a rotation of a helical hairpin at the Sos catalytic site. This motion relieves steric occlusion of the catalytic site, allowing substrate Ras binding and nucleotide exchange. A structure of the isolated RasGRF1 Cdc25 domain determined at 2.2-A resolution, combined with computational analyses, suggests that the Cdc25 domain of RasGRF1 is able to maintain an active conformation in isolation because the helical hairpin has strengthened interactions with the Cdc25 domain core. These results indicate that RasGRF1 lacks the allosteric activation switch that is crucial for Sos activity.
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