Closing the lid on the mono‐ADP‐ribosylating reaction mechanism by bacterial toxins
Bibliographic record
Abstract
The bacteria causing diphtheria, whooping cough, cholera and other human diseases secrete mono‐ADP‐ribosylating toxins that modify intracellular proteins in the target host eukaryotic cell. Recently, we solved four crystal structures of a catalytically active complex between the enzyme domain of Exotoxin A (ETA) and its protein substrate, elongation factor 2 (eEF2), which has led to a breakthrough in the understanding of the reaction mechanism of this family of deadly toxins. The target residue in eEF2, a modified histidine called diphthamide, spans across a cleft in the complex and faces the two phosphates of the NAD + analogue, βTAD. This suggests that the diphthamide is involved in triggering NAD + cleavage and is interacting with the proposed oxacarbenium intermediate during the nucleophilic substitution reaction. Notably, the βTAD phosphates mimic the phosphate backbone of two nucleotides in a conformational switch of 18S rRNA, thereby achieving universal recognition of eEF2 by ETA. However, the structures do not reveal the transition state for the transferase reaction within the complex. We have new data showing that there are catalytic residues located within an active‐site loop of the toxin. We propose that this loop is in an open conformation in the protein complex structures and during transition‐state formation closes in on the active site partly as a cover for solvents and partly to help stabilize the oxacarbenium ion.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.001 | 0.002 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.002 |
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".