Faculty Opinions recommendation of Structural basis for gating pore current in periodic paralysis.
Bibliographic record
Abstract
Potassium-sensitive Hypokalemic and Normokalemic Periodic Paralysis (HypoPP, NormoPP) are inherited skeletal muscle diseases characterized by episodes of flaccid muscle weakness 1,2 .They are caused by mutations in one gating charge in an S4 transmembrane segment in the voltage sensor (VS) of voltage-gated sodium channel Na v 1.4 or calcium channel Ca v 1.1 1,2 .Mutations of the outermost arginine gating charges (R1 and R2) cause HypoPP 1,2 by creating a pathogenic gating pore in the VS through which cations leak in the resting state 3,4 .Mutations of the third arginine gating charge (R3) cause NormoPP 5 owing to cationic leak in activated/inactivated states 6 .Here we present high-resolution structures of these pathogenic gating pores in the model bacterial sodium channel Na V Ab 7,8 .Mutation of R2 in Na V Ab gives gating pore current in resting states, whereas mutation of R3 gives gating pore current in activated/inactivated states.Mutations R2G and R3G have no effect on backbone structures of VS, but create aqueous space near the hydrophobic constriction site (HCS) that controls gating charge movement through VS.The R3G mutation extends the extracellular aqueous cleft completely through the activated VS.Although the R2G mutation does not create a continuous aqueous pathway in the activated state, molecular modeling of the resting state reveals a complete water-accessible pathway.Crystal structures of Na V Ab/R2G in complex with guanidinium define a potential drug target site.Molecular dynamics simulations illustrate the mechanism of Na + permeation through the mutant gating pore in concert with conformational fluctuations of gating charge R4.Our results reveal pathogenic mechanisms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research,
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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 | 0.001 | 0.004 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.003 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.007 | 0.003 |
| Insufficient payload (model declined to judge) | 0.480 | 0.294 |
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".