Defining the dynamics behind ryanodine receptor modulation by small molecules
Bibliographic record
Abstract
Ryanodine receptors (RyRs) are calcium release channels that mediate the rapid release of calcium from the endoplasmic/sarcoplasmic reticulum into the cytosol. RyRs are essential for excitation-contraction coupling and are modulated by numerous auxiliary proteins and small molecules. There are over 200 reported mutations within the channel's skeletal isoform (RyR1) associated with altered channel function. However the molecular mechanism by which these mutations influence RyR1 response to channel's many modulators remains unclear. We employed mass spectrometry and cryo-electron microscopy to identify the direct and long-range allosteric consequences of ligand binding within RyR1. We determined that ligand binding within RyR1 regions, despite being distinct from mutated residue, are likely responsible for the altered function. These findings further support that significant long-range cooperatively across RyR1 domains is required for normal channel activity.
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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 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".