Tunable Bias Signaling of the Angiotensin II Type 1 Receptor for Inotropy via C-Terminal Peptide Modifications and Allosteric Site Targeting
Bibliographic record
Abstract
ABSTRACT The angiotensin II (AngII) type 1 receptor (AT1R) is a key prototypical G protein-coupled receptor in cardiovascular regulation. Biased agonists that activate G protein or β-arrestin pathways provide promising therapeutic potential, but the molecular determinants for this signaling bias and its physiological implications remain poorly understood. This study profiles AngII analogs with modifications at the C-terminal Phe 8 , revealing that analogs 11 , 12 , and 29a exhibit varying degrees of Gα q engagement while maintaining potent β-arrestin recruitment. Notably, 12 enhances left ventricular ejection fraction with minimal pressor responses in normotensive rats, while other analogs with variable Gα q activity do not promote inotropy. Molecular modeling indicates that the unique profile of 12 results from its flexible long side chain engaging a deep allosteric pocket within AT1R. This study demonstrates that engineering AngII’s C-terminus enables selective tuning of AT1R signaling to control arterial versus cardiac responses, providing strategies for developing improved cardiovascular therapeutics. GRAPHICAL ABSTRACT
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.012 | 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".