Three-Dimensional Structure of the Argininosuccinate Lyase Frequently Complementing Allele Q286R<sup>,</sup>
Bibliographic record
Abstract
Argininosuccinate lyase (ASL) catalyzes the reversible breakdown of argininosuccinate to arginine and fumarate, a reaction involved in the biosynthesis of arginine in all species and in the production of urea in ureotelic species. In humans, mutations in the enzyme result in the autosomal recessive disorder argininosuccinic aciduria. Intragenic complementation has been demonstrated to occur at the ASL locus, with two distinct classes of ASL-deficient strains having been identified, the frequent and high-activity complementers. The frequent complementers participate in the majority of the complementation events observed and were found to be either homozygous or heterozygous for a glutamine to arginine mutation at residue 286. The three-dimensional structure of the frequently complementing allele Q286R has been determined at 2.65 A resolution. This is the first high-resolution structure of human ASL. Comparison of this structure with the structures of wild-type and mutant duck delta1 and delta2 crystallins suggests that the Q286R mutation may sterically and/or electrostatically hinder a conformational change in the 280's loop (residues 270-290) and domain 3 that is thought to be necessary for catalysis to occur. The comparison also suggests that residues other than R33, F333, and D337 play a role in maintaining the structural integrity of domain 1 and reinforces the suggestion that residues 74-89 require a particular conformation for catalysis. The electron density has enabled the structure of residues 6-18 to be modeled for the first time. Residues 7-9 and 15-18 are in type IV beta-turns and are connected by a loop. The conformation observed is stabilized, in part, by a salt bridge between the side chains of R12 and D18. Although the disease causing mutation R12Q would disrupt this salt bridge, it is unclear why this mutation has such a significant effect on the catalytic activity as residues 1-18 are disordered in all other delta-crystallin structures determined to date.
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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 | 0.000 | 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".