A metal‐dependent conformational change provides a structural basis for the inhibition of CTP synthase by gemcitabine‐5′‐triphosphate
Bibliographic record
Abstract
Abstract CTP synthases (CTPS) catalyze the de novo production of CTP using UTP, ATP, and l ‐glutamine with the anticancer drug metabolite gemcitabine‐5′‐triphosphate (dF‐dCTP) being one of its most potent nucleotide inhibitors. To delineate the structural origins of this inhibition, we solved the structures of Escherichia coli CTPS ( ec CTPS) in complex with CTP (2.0 Å), 2′‐ ribo ‐F‐dCTP (2.0 Å), 2′‐ arabino ‐F‐CTP (2.4 Å), dF‐dCTP (2.3 Å), dF‐dCTP and ADP (2.1 Å), and dF‐dCTP and ATP (2.1 Å). These structures revealed that the increased binding affinities observed for inhibitors bearing the 2′‐F ‐arabino group (dF‐dCTP and F‐araCTP), relative to CTP and F‐dCTP, arise from interactions between the inhibitor's fluorine atom exploiting a conserved hydrophobic pocket formed by F227 and an interdigitating loop from an adjacent subunit (Q114‐V115‐I116). Intriguingly, crystal structures of ec CTPS•dF‐dCTP complexes in the presence of select monovalent and divalent cations demonstrated that the in crystallo tetrameric assembly of wild‐type ec CTPS was induced into a conformation similar to inhibitory ec CTPS filaments solely through the binding of Na + ‐, Mg 2+ ‐, or Mn 2+ •dF‐dCTP. However, in the presence of potassium, the dF‐dCTP‐bound structure is demetalated and in the low‐affinity, non‐filamentous conformation, like the conformation seen when bound to CTP and the other nucleotide analogues. Additionally, CTP can also induce the filament‐competent conformation linked to high‐affinity dF‐dCTP binding in the presence of high concentrations of Mg 2+ . This metal‐dependent, compacted CTP pocket conformation therefore furnishes the binding environment responsible for the tight binding of dF‐dCTP and provides insights for further inhibitor design.
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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 | 0.001 | 0.001 |
| 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".