The structural basis of allosteric communication networks of Ras GTPases and their oncogenic mutants
Bibliographic record
Abstract
The Ras superfamily of small GTPases are centrally involved critical cellular processes, including cell proliferation, differentiation, and survival. Ras proteins function through a molecular switch mechanism, and in the active GTP-bound state can signal to downstream partners, regulated by GEFs. Deactivation is achieved through GAP activation allowing for hydrolysis of GTP, and disruption to hydrolysis leads to overstimulation of pathways such as Ras/Raf/MEK/ERK which causes cancer. H-Ras features a distant allosteric site that interacts with GTP at the active site via a water-mediated hydrogen bonding network. Discovery of this site has led to the investigation of the role of intrinsic hydrolysis promoted by Raf. In its activated form, Ras samples conformational states which differ among the isoforms, and is influenced by point mutations, leading to varying outcomes despite their ~85% sequence identity. Initially, it was assumed that H-Ras was a suitable model for the other isoforms, and thus is represented prominently in the literature. However, K-Ras is more frequently mutated, and we have discovered differences in the highly conserved active sites of the isoforms. To gain a greater understanding of the mechanisms driving these differences, MD simulations were compared to experimental data, and analyzed for accessibility to specific conformational states. We also apply MD simulations to K-Ras oncogenic mutations which have been shown to favor specific conformations that are hypothesized promote overactivation of downstream pathways. To gain a greater understanding of K-Ras compared to H-Ras, we obtained 1NMR resonance peaks associated with sensors of the active site. To assess the conformational states, we designed a mutant that more readily accesses the catalytically competent state of Ras, as opposed to other mutations which more readily access more disordered conformation within state 2. From there, exploration of the protonation state of GTP in the Ras mechanism and the insights of the conformational states in the isoforms are tested in superfamily member Arf1. These efforts can possibly inform drug discovery targeting efforts about unique states accessed by mutations of K-Ras and other Ras superfamily proteins.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".