Critical Hydrogen Bond Formation for Activation of the Angiotensin II Type 1 Receptor
Bibliographic record
Abstract
G protein-coupled receptors contain selectively important residues that play central roles in the conformational changes that occur during receptor activation. Asparagine 111 (N111 3.35 ) is such a residue within the angiotensin II type 1 (AT 1 ) receptor. Substitution of N111 3.35 for glycine leads to a constitutively active receptor, whereas substitution for tryptophan leads to an inactivable receptor. Here, we analyzed the AT 1 receptor and two mutants (N111G and N111W) by molecular dynamics simulations, which revealed a novel molecular switch involving the strictly conserved residue D74 2.50 . Indeed, D74 2.50 forms a stable hydrogen bond (H-bond) with the residue in position 111 3.35 in the wild-type and the inactivable receptor. However, in the constitutively active mutant N111G-AT 1 receptor, residue D74 is reoriented to form a new H-bond with another strictly conserved residue, N46 1.50 . When expressed in HEK293 cells, the mutant N46G-AT 1 receptor was poorly activable, although it retained a high binding affinity. Interestingly, the mutant N46G/N111G-AT 1 receptor was also inactivable. Molecular dynamics simulations also revealed the presence of a cluster of hydrophobic residues from transmembrane domains 2, 3, and 7 that appears to stabilize the inactive form of the receptor. Whereas this hydrophobic cluster and the H-bond between D74 2.50 and W111 3.35 are more stable in the inactivable N111W-AT 1 receptor, the mutant N111W/F77A-AT 1 receptor, designed to weaken the hydrophobic core, showed significant agonist-induced signaling. These results support the potential for the formation of an H-bond between residues D74 2.50 and N46 1.50 in the activation of the AT 1 receptor. Background: The N111G and N111W mutations make the AT 1 receptor constitutively active and inactivable, respectively. Results: The orientation and interactions of D74 2.50 are influenced by the residue at position 111 3.35 . Conclusion: H-bond formation between D74 2.50 and N46 1.50 is critical for AT 1 receptor activation. Significance: This novel molecular switch could be involved in the GPCR activation mechanism as it involves highly conserved residues D 2.50 and N 1.50 .
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.002 | 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".