Abstract 2790: Localization of the binding site for Peloruside A and Laulimalide on beta-tubulin by physical and biological means
Bibliographic record
Abstract
Abstract Peloruside A (Pel) and laulimalide (Laul) are microtubule-stabilizing natural products that were discovered recently compared to more established agents such as the taxanes and the epothilones. The activities of Pel and Laul are synergistic with taxanes or epothilones but not with each other, indicating separate binding sites and distinct mechanisms for Pel and Laul compared to taxanes and epothilones. Hence the location and nature of the Pel / Laul binding site is of interest. We have identified this site by a physical method (mass spec H-D footprinting) and a biological one: isolating Pel-resistant mutants of human ovarian carcinoma cells (A2780 (1A9)). Four Pel-resistant lines were obtained with single-base mutations in class I β-tubulin which resulted in the following substitutions: R306H, Y340S, N337D, and A296S in various combinations. The mutations localize to the peptides identified by the mass spec method, and center on a cleft in which modeling indicates that the Pel and Laul side chains dock. The site is accessible from the outside of the microtubule and does not overlap the Taxol site on β-tubulin. The Pel resistant lines are cross resistant to Laul, but not to any other microtubule stabilizing drug, and show no cross-sensitivity to microtubule destabilizing drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2790. doi:1538-7445.AM2012-2790
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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) | 0.004 | 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".