Asynchronous subunit transitions precede acetylcholine receptor activation
Bibliographic record
Abstract
Rapid communication at synapses is facilitated by postsynaptic receptors, which convert a chemical signal into an electrical response. In the case of ligand-gated ion channels, agonist binding triggers rapid transition through a series of intermediate states leading to a transient open-pore conformation. These transitions are usually framed in terms of a mechanism where agonist binding and channel activation are separate events. Here, we collect cryo-EM images over a range of agonist concentrations to define structures of the muscle-type nicotinic acetylcholine receptor in unliganded, mono-liganded, and di-liganded states. We show that agonist binding to a single agonist site stabilizes an intermediate state where an entire principal agonist-binding subunit has transitioned to an active-like conformation, while the other unoccupied principal subunit remains inactive, albeit poised for activation. Binding of agonist to the second agonist site fully activates the remaining subunits leading to hydration of the ion pore. Uniting this cryo-EM derived intermediate structure with single-channel recordings leads to a model where individual acetylcholine receptor subunits asynchronously undergo conformational transitions, and thus a sequential activation mechanism that has implications for the entire superfamily of pentameric ligand-gated ion channels.
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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 | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".