The structural basis of the activation of Ras by Sos
Abstract
The crystal structure of human H-Ras complexed with the Ras guanine-nucleotide-exchange-factor region of the Son of sevenless (Sos) protein has been determined at 2.8 A resolution. The normally tight interaction of nucleotides with Ras is disrupted by Sos in two ways. First, the insertion into Ras of an alpha-helix from Sos results in the displacement of the Switch 1 region of Ras, opening up the nucleotide-binding site. Second, side chains presented by this helix and by a distorted conformation of the Switch 2 region of Ras alter the chemical environment of the binding site for the phosphate groups of the nucleotide and the associated magnesium ion, so that their binding is no longer favoured. Sos does not impede the binding sites for the base and the ribose of GTP or GDP, so the Ras-Sos complex adopts a structure that allows nucleotide release and rebinding.
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Developing KRAS inhibitors targeting SOS is considered a viable alternative strategy for countering KRAS mutations.
“Therefore, developing KRAS inhibitors targeting SOS is considered a viable alternative strategy for countering KRAS mutations.332”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [332]
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- Authors
- Boriack-Sjodin, P. A., Margarit, S. M., Bar-Sagi, D., & Kuriyan, J.
- Affiliations
- State University of New York (US)
- Howard Hughes Medical Institute (US)
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- Kuriyan, John
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- 1998-07
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- 394
- Issue
- 6691
- Pages
- 337-343
- ISSN
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- 1476-4687
- OpenAlex
- W1824220821
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- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- Ras activation, SO, Son of Sevenless, H-Ras, guanine nucleotide exchange factor, crystal structure, nucleotide binding site, GTP binding, GDP binding, nucleotide release
- MeSH terms
- Binding Sites, Catalysis, Cloning, Molecular, Escherichia coli, Guanine, Guanosine Triphosphate, Humans, Membrane Proteins, Models, Molecular, Molecular Sequence Data, Mutation, Peptide Elongation Factor Tu, Peptide Elongation Factors, Protein Binding, Protein Conformation, Structure-Activity Relationship, Crystallography, X-Ray, ras Proteins, Son of Sevenless Proteins, GTP Phosphohydrolase-Linked Elongation Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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