Elucidation of Structural Mechanism of ATP Inhibition at the AAA1 Subunit of Cytoplasmic Dynein 1 Using a Chemical “Toolkit”
Bibliographic record
Abstract
Abstract Dynein is a cytoskeletal motor protein that carries organelles via retrograde transport in eukaryotic cells. The motor protein belongs to the ATPase family of proteins associated with diverse cellular activities and plays a critical role in transporting cargoes to the minus end of the microtubules. The motor domain of dynein possesses a hexameric head, where ATP hydrolysis occurs. The AAA1 binding site is the leading ATP hydrolytic site, followed by the AAA3 subsite. Small-molecule ATP competitive inhibitors of dynein are thought to target the AAA1 site. The presented work elucidates the structure-activity relationship of dynapyrazole A and B, ciliobrevin A and D in their various protonated states and their 46 analogs for their binding properties in the nucleotide-binding site of the AAA1 subunit and their effects on the functionally essential subsites of the motor domain of cytoplasmic dynein 1, as there is currently no similar experimental structural data available. Ciliobrevin and its analogs bind to the ATP motifs of the AAA1, namely the Walker-A or P-loop, the Walker-B, and the sensor I and II. Ciliobrevin A shows a better binding affinity to the AAA1 binding site of dynein 1 than its D analog. Although the double bond in ciliobrevin A and D was expected to decrease the ligand potency, they show a better affinity to the AAA1 binding site than dynapyrazole A and B, lacking the bond. Protonation of the nitrogen in ciliobrevin A, D, dynapyrazole A, and B at the N9 site of ciliobrevin, and the N7 of the latter increased their binding affinity. Exploring ciliobrevin A geometrical configuration suggests the E isomer has a superior binding profile over the Z due to binding at the critical ATP motifs. Utilizing the refined structure of the motor domain obtained through protein conformational search in this study exhibits that Arg1852 of the yeast cytoplasmic dynein could involve in the “glutamate switch” mechanism in cytoplasmic dynein 1 in lieu of the conserved Asn in AAA+ protein family, as the guanidine moiety of the Arg engages in an H-bond with the carboxylate moiety of Glu1849.
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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".