Structures of microfilament destabilizing toxins bound to actin provide insight into toxin design and activity
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
Marine macrolides that disrupt the actin cytoskeleton are promising candidates for cancer treatment. Here, we present the actin-bound x-ray crystal structures of reidispongiolide A and C and sphinxolide B, three marine macrolides found among a recently discovered family of cytotoxic compounds. Their structures allow unequivocal assignment of the absolute configuration for each compound. A comparison of their actin-binding site to macrolides found in the trisoxazole family, as well as the divalent macrolide, swinholide A, reveals the existence of a common binding surface for a defined segment of their macrocyclic ring. This surface is located on a hydrophobic patch adjacent to the cleft separating domains 1 and 3 at the barbed-end of actin. The large area surrounding this surface accommodates a wide variety of conformations and designs observed in the macrocyclic component of barbed-end-targeting macrolides. Conversely, the binding pocket for the macrolide tail, located within the cleft itself, shows very limited variation. Functional characterization of these macrolides by using in vitro actin filament severing and polymerization assays demonstrate the necessity of the N-methyl-vinylformamide moiety at the terminus of the macrolide tail for toxin potency. These analyses also show the importance of stable interactions between the macrocyclic ring and the hydrophobic patch on actin for modifying filament structure and how this stability can be compromised by subtle changes in macrolactone ring composition. By identifying the essential components of these complex natural products that underlie their high actin affinity, we have established a framework for designing new therapeutic agents.
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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 | 0.001 | 0.002 |
| 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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 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 it