Crystal structure of thermostable aspartase and exploration of functional sites in aspartase family
Bibliographic record
Abstract
Due to the prolific use and abuse of antibiotics, pathogenic bacteria have evolved means to render these drugs ineffective. Resistant bacteria can counter the effects of antibiotics in several ways. For aminoglycosides, a group of bactericidal antibiotics that target the A-site of the 16S ribosomal RNA, the most common mode of resistance is enzyme-catalyzed chemical modification and detoxification of the drug. Aminoglycoside kinase (3') type IIIa (APH(3')-IIIa), an enzyme produced by pathogenic Gram-positive bacteria such as Enterococci and Staphylococci, is capable of conferring resistance to at least ten clinically important aminoglycoside antibiotics. In an effort to understand the promiscuity in substrate recognition by APH(3')-IIIa, we have determined the crystal structures, by molecular replacement, of APH(3')-IIIa in complex with ADP and kanamycin A, ADP and neomycin B, and AMPPNP (an ATP analog) and butirosin A. Refinement for the kanamycin and neomycin enzyme complexes have been completed to 2.4 and 2.7 angstroms with R-factors 0.234 and 0.219, respectively. Refinement for enzyme complexed with butirosin is in progress. These structures reveal that the basis for this enzyme's broad substrate spectrum is the presence of a flexible antibiotic-binding loop and a versatile antibiotic-binding pocket composed of three sub-sites. Comparison between the A site of the bacterial ribosome and APH(3')-IIIa shows a high degree of similarity in the pattern of hydrogen bonds to the aminoglycoside. However, they differ in their van der Waals interactions with the substrate, suggesting a potential strategy for the design and development of novel antibiotics and adjuvants.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| 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".