Molecular and pharmacological characterization of an acetylcholine-gated chloride channel (ACC-2) from the parasitic nematode Haemonchus contortus
Bibliographic record
Abstract
Nematode cys-loop ligand-gated ion channels (LGICs) have been shown to be attractive targets for the development of novel anti-parasitic drugs. The ACC-1 family of receptors are a unique group of acetylcholine-gated chloride channels present only in invertebrates, and sequence analysis suggests that they contain a novel binding site for acetylcholine. We have isolated a novel member of this family, Hco-ACC-2, from the parasitic nematode Haemonchus contortus and using site-directed mutagenesis, electrophysiology and molecular modelling examined how two aromatic amino acids in the binding site contributed to agonist recognition. It was found that instead of a tryptophan residue in binding loop B, which essential for ligand binding in mammalian nAChRs, there is a phenylalanine (F200) in Hco-ACC-2. Amino acid changes at F200 to either a tyrosine or tryptophan were fairly well tolerated, where a F200Y mutation resulted in a channel hypersensitive to ACh and nicotine as well as other cholinergic agonists such as carbachol and methacholine. In addition, both pyrantel and levamisole were partial agonists at the wild-type receptor and like the other agonists showed an increase in sensitivity at F200Y. On the other hand, in Hco-ACC-2 there is a tryptophan residue at position 248 in loop C that appears to be essential for receptor function, as mutations to either phenylalanine or tyrosine resulted in a marked decrease in agonist sensitivity. Moreover, mutations that swapped the residues F200 and W248 (ie. F200W/W248F) produced non-functional receptors. Overall, Hco-ACC-2 appears to have a novel cholinergic binding site that could have implications for the design of specific anthelmintics that target this family of receptors in parasitic nematodes.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".