Photolabeling of Tissue Transglutaminase Reveals the Binding Mode of Potent Cinnamoyl Inhibitors
Bibliographic record
Abstract
We have recently developed a new class of cinnamoyl derivatives as potent tissue transglutaminase (TG2) inhibitors. Herein, we report the synthesis of a diazirine derivative of these inhibitors and its application to the photolabeling of its binding site on guinea pig liver transglutaminase. Two novel homology models were generated for this commonly studied TG2, which differ in the conformational state they represent. Tryptic digest and mass spectrometric analysis of the photolabeling experiment showed that only residue Cys230 was labeled, and our homology models were used to visualize these results. This visualization suggested that Cys230 is somewhat more solvent-exposed in the "closed" conformation of TG2, compared to the "open" conformation. Docking experiments suggested binding modes consistent with the labeling pattern that would block access to the tunnel leading to the active site, consistent with the observed mode of inhibition. However, while these modeling simulations favored the closed conformation as the target of our cinnamoyl inhibitors, native PAGE experiments indicated the open conformation of the enzyme in fact predominates in the presence of our photolabeling derivative. These results are important for understanding the binding modes of TG2 inhibitors in general and will be critical for the structure-based design of future inhibitors.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".