Structural basis for the tight binding inhibition of <i>E. coli</i> CTP synthase inhibition by gemcitabine and its analogues
Bibliographic record
Abstract
CTP synthase (CTPS) is a vital metabolic enzyme which controls the pyrimidine nucleotide pool by converting UTP into CTP with the use of ATP and ammonia. The E coli. variant is tightly regulated by the available nucleotides, where it is allosterically modulated by GTP and CTP. CTP binding can induce inhibitory filament formation, whereas the human isozyme forms active filaments upon UTP binding. Due to the in vivo importance of CTPS, variable regulatory mechanism across species, and previous data suggesting it is vital to the maintenance of various disease states, selective inhibition of CTPS may be a fruitful avenue to develop treatments for some of these illnesses. Most recently, a series of fluorinated CTP analogues were characterized for their inhibition against CTPS. Of these molecules, a doublely fluorinated at the 2' position of the ribose moiety had an at least 30x increased inhibition over its monofluorinated counterparts. Here, we determined the crystal structures of the various fluorinated inhibitors of CTPS to determine the molecular interactions and conformational changes contributing to the potent inhibition of the enzyme by these nucleotide analogues.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".