Transmembrane Domains IV and V Form an Interface in Human Angiotensin II Type 1 Receptor Homomers
Bibliographic record
Abstract
Of the 750 GPCRs said to be expressed in humans, only approximately 20 individual high-resolution crystal structures are available for human GPCRs. While GPCR oligomerization is a common occurrence, very few groups have had success in crystallizing these structures. Given the fact that the pharmacology of these entities has been shown to diverge from that of their monomeric constituents, there has been a push for biophysical characterization of GPCR oligomers. Here, we sought to characterize the structure of human angiotensin II type 1 receptor (AT1R) homomers with a bioluminescence resonance energy transfer (BRET)-based approach. An initial alignment was performed, and we developed a three-dimensional homology model of the AT1R using the GPCR Online MOdeling and DOcking server. The δ-opioid receptor (DOR) was selected as the best template for AT1R homology modeling using two scoring functions. This model received a normalized Discrete Optimized Protein Energy (DOPE) score of 0.03223 and a GA341 score of 0 (Fig.1). Accessible surface area was determined for each side chain in the modelled AT1R transmembrane (TM) region. This data, as well as published data surrounding the DOR,allowed us to focus our efforts on discrete AT1R TM regions. Site-directed mutagenesis and BRET experiments identified an AT1R homomer interface at TM domains IV and V (Fig.2). This was validated using GPCR Heteromer Identification Technology. These results contribute to our understanding of AT1R dimerization and may serve as the foundation for future drug discovery efforts that target GPCR oligomers. Supported by the Natural Sciences and Engineering Research Council of Canada.
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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".