ArticleProceedings of the National Academy of Sciences of the United States of America2010
Allosteric modulation of Ras positions Q61 for a direct role in catalysis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 142 papers.
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Who cites it
142 citing papers in PubMed, 245 citations in OpenAlex.
- Computational identification and characterization of high-risk human KRAS nsSNPs: Impacting structure, ligand binding, and cancer prognosis.Journal, genetic engineering & biotechnology · 2026Article
- Brønsted-basic small molecules activate GTP hydrolysis in KRAS-Q61 mutants.Nature chemical biology · 2026Article
- KRAS signaling networks, mutational heterogeneity, and emerging therapeutic strategies for cancer treatment.Biomarker research · 2026Review
- Alternative Splicing of a Structured Partner Alters the Folding-Upon-Binding Trajectory of an Intrinsically Disordered Protein.Journal of the American Chemical Society · 2026Article
- Divergent CRD-Dependent Mechanisms Govern RAS Isoform-Selective Recruitment of CRAF and ARAF.bioRxiv : the preprint server for biology · 2026Article
- Posttranslational modifications remodel proteome-wide ligandability.Nature chemical biology · 2026Article
- An evolutionarily conserved salt bridge stabilizes the active site for GTP hydrolysis in Rho GTPases.The Journal of biological chemistry · 2026Article
- Article
- Targeting oncogenic K-RAS mutants with small-molecule degrader XMU-MP-9 through NEDD4-1.Acta pharmaceutica Sinica. B · 2026Article
- Article
- Direct Inhibition of RAS Reveals the Features of Oncogenic Signaling Driven by RAS G12 and Q61 Mutations.Cancer discovery · 2025Article
- The C2 domain augments Ras GTPase-activating protein catalytic activity.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Distinct association of HRAS and KRAS with MnMagnetic resonance letters · 2025Article
- Novel inhibitors of the (VIBVN) NAT protein identified through pharmacophore modeling.Scientific reports · 2025Article
- Article
- Insight into structural dynamics involved in activation mechanism of full length KRAS wild type and P-loop mutants.Heliyon · 2024Article
- Functional distinction in oncogenic Ras variant activity in Caenorhabditis elegans.Disease models & mechanisms · 2024Article
- Article
- GTP-Bound N-Ras Conformational States and Substates Are Modulated by Membrane and Point Mutation.International journal of molecular sciences · 2024Article
- Allosteric site variants affect GTP hydrolysis on Ras.Protein science : a publication of the Protein Society · 2023Article
82 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Ras and its effector Raf are key mediators of the Ras/Raf/MEK/ERK signal transduction pathway. Mutants of residue Q61 impair the GTPase activity of Ras and are found prominently in human cancers. Yet the mechanism through which Q61 contributes to catalysis has been elusive. It is thought to position the catalytic water molecule for nucleophilic attack on the gamma-phosphate of GTP. However, we previously solved the structure of Ras from crystals with symmetry of the space group R32 in which switch II is disordered and found that the catalytic water molecule is present. Here we present a structure of wild-type Ras with calcium acetate from the crystallization mother liquor bound at a site remote from the active site and likely near the membrane. This results in a shift in helix 3/loop 7 and a network of H-bonding interactions that propagates across the molecule, culminating in the ordering of switch II and placement of Q61 in the active site in a previously unobserved conformation. This structure suggests a direct catalytic role for Q61 where it interacts with a water molecule that bridges one of the gamma-phosphate oxygen atoms to the hydroxyl group of Y32 to stabilize the transition state of the hydrolysis reaction. We propose that Raf together with the binding of Ca(2+) and a negatively charged group mimicked in our structure by the acetate molecule induces the ordering of switch I and switch II to complete the active site of Ras.
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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.