Bibliographic record
Abstract
Amino acids act as either orthosteric agonists or as positive allosteric modulators of Family C G-protein coupled receptors (GPCRs). Family C receptors can be categorized into two primary groups based on amino acid sensitivity. A group that includes the metabotropic glutamate receptors (mG1uRs) was activated solely by L-glutamate, while a second group that includes an array of chemosensory receptors, responded to a broad spectrum of amino acid ligands. Phylogenetic analysis suggested an early separation of these two lineages of receptors. Two receptors in the latter class, the fish 5.24 receptor, and its putative mammalian orthologue, GPRC6A, both displayed a broad amino acid activation profile and a preference for basic amino acids. The molecular basis for ligand selectivity in Family C receptors was explored using amino acid sequence alignments, molecular modeling, mutagenesis, radioligand binding, and functional assays. Four conserved residues in the ligand binding pockets that interact with the alpha-amino group of the bound ligands are essential for amino acid recognition. Three additional sites at positions 78, 310, and 389 (numbering as in the 5.24 receptor) that establish bonds with the side-chain of the ligands are the primary determinants of amino acid selectivity within the family. An approach using "ancestral reconstruction" in order to trace the evolutionary history of molecular changes in protein structure, was carried out on the 5.24 receptor background. Using this approach, the ancestral residues at positions 78, 310, and 389 were inferred to be arginine, alanine, and isoleucine respectively. The pharmacological profile of the ancestral receptor displayed high affinity for L-glutamate and Group I mGluR-specific agonists. These findings suggested that the ancestral receptor of Family C GPCRs may have been pre-adapted for use in glutamate-mediated neurotransmission. Our results also suggest that this feature was further refined in the mGluR subfamily during evolution whereby the Group I mGluRs (mGluR1 and mGluR5) may have retained a more primitive configuration of the binding pocket compared to the other six mGluR receptor subtypes.
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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) | 0.003 | 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".