Insight into mosquito GnRH-related neuropeptide receptor specificity revealed through analysis of naturally occurring and synthetic analogs of this neuropeptide family
Bibliographic record
Abstract
Abstract Adipokinetic hormone (AKH), corzazonin (CRZ) and the AKH/CRZ-related peptide (ACP) are peptides considered homologous to the vertebrate gonadotropin-releasing hormone (GnRH). All three Aedes aegypti GnRH-related neuropeptide receptors have been characterized and functionally deorphanized, which individually exhibit high specificity for their native ligands, which prompted us to investigate the contribution of ligand structures in conferring receptor specificity. In the current study, we designed a series of analogs based on the native ACP sequence in A. aegypti and screened them against the ACP receptor using a heterologous system to identify critical residues required for receptor activation. Specifically, analogs lacking the carboxy-terminal amidation, replacing aromatic residues, as well as truncated analogs were either completely inactive or had very low activities even at high concentration. The next most critical residues were the polar threonine in position 3 and the blocked amino-terminal pyroglutamate, with activity of the latter partially recovered using an alternatively blocked analog. ACP analogs with alanine substitutions at position 2 (valine), 5 (serine), 6 (arginine) and 7 (aspartic acid) positions were less detrimental as were replacements of charged residues. Interestingly, replacing asparagine with an alanine at position 9, creating a C-terminal WAA-amide, resulted in a 5-fold more active analog which may be useful as a lead superagonist compound. Similarly, we utilized this high-throughput approach against an A. aegypti AKH receptor (AKHR-IA) testing a number of mostly naturally-occurring AKH analogs from other insects to determine how substitutions of specific amino acids in the AKH ligand influences receptor activation. AKH analogs having single substitutions compared to the endogenous A. aegypti AKH revealed position 7 (serine) was well tolerated whereas changes to position 6 (proline) had pronounced effects, with receptor activity compromised nearly ten-fold. Substitution of position 3 (threonine) or analogs with combinations of substitutions were quite detrimental with a significant decrease in AKHR-IA activation. Interestingly, analogs with an asparagine residue at position seven displayed improved receptor activation compared to the native mosquito AKH. Collectively, these results advance our understanding of how two GnRH-related systems in A. aegypti sharing the most recent evolutionary origin sustain independence of function and signalling despite their relatively high degree of ligand and receptor homology.
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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 | 0.000 |
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".