Transmembrane Domain V of the Endothelin-A Receptor Is a Binding Domain of ET<sub>A</sub>-Selective TTA-386-Derived Photoprobes
Bibliographic record
Abstract
On the basis of the structure of TTA-386, a specific antagonist of the endothelin-A receptor subtype (ET(A)), photosensitive analogues were developed to investigate the binding domain of the receptor. Among those, a derivative containing, in position 6, the photoreactive amino acid D- or L-p-benzoyl-phenylalanine showed pharmacological properties very similar to those of TTA-386. Affinity of the probes were also evaluated on transfected CHO cells overexpressing the human ET(A) receptor. Data showed that binding of the radiolabeled peptides were inhibited by ET-1 and BQ-610. Therefore, these photolabile probes were used to label the ET(A) receptor found in CHO cells. Photolabeling produced a ligand-protein complex appearing on SDS-PAGE at around 66 kDa. An excess of ET-1 or BQ-610 completely abolished the formation of the complex showing the selectivity of the photoprobes. Digestions of the [125I-Tyr5, D- or L-Bpa6]TTA-386-ET(A) complex were carried out, and receptor fragments were analyzed to define the region of the receptor where the ligand interacted. Results showed that Endo Lys-C digestion gave a 4.8 kDa fragment corresponding to the Asp256-Lys299 segment, whereas migration after V8 digestion revealed a fragment of 2.9 kDa. Because the fragments of these two digestions must overlap, the latter would be the Trp257-Glu281 stretch. A cleavage with CNBr confirmed the identity of the binding domain by giving a fragment of 3.9 kDa corresponding to Glu249-Met278. Thus, the combined cleavage data strongly suggested that the binding domain of ET(A) includes a portion of the fifth transmembrane domain, between residues Trp257 and Met278.
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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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".