Gating Mechanism for Biased Agonism at Angiotensin II Type 1 Receptors
Bibliographic record
Abstract
For the interaction of angiotensin II (AngII) with AngII type 1 receptors (AT1R), two potential proton hopping pathways have been identified, each associated with distinct physiological outcomes. The octapeptide AngII (Asp1-Arg2-Val3-Tyr4-Ile5-His6-Pro7-Phe8) appears to form a charge relay system (CRS) in solution in which the C-terminal carboxylate abstracts a proton from the His6 imidazole group, which, in turn, abstracts a proton from the Tyr4 hydroxyl (OH) group, creating a tyrosinate anion. When AngII binds to the AT1R, the CRS can be reconstituted with D281 of the receptor taking up the role of the Phe8 carboxylate in the tripartite interaction, whilst the Phe8 carboxylate forms a salt bridge with K199 of the receptor. As a consequence, the Tyr4 OH of AngII is positioned with accessibility to either the Phe8 carboxylate (bound to K199) or the His6 imidazole (activated by D281), thereby creating a potential gating mechanism for AT1R receptor signaling. This study summarizes evidence based on structure activity data for various analogs wherein Tyr4 OH interaction with His6 imidazole (CRS formation) leads to G protein sequestration and vasoconstriction, whereas Tyr4 OH interaction with Phe8 carboxylate (bound to K199) engenders arrestin-mediated vasodilation and receptor desensitization. These findings, combined with quantum mechanical (semiempirical) calculations of CRS proton transfer presented herein, provide insights for the therapeutic targeting of angiotensin receptor blockers (sartans) and the development of second-generation drugs (bisartans).
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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 | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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 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".