Allosteric regulation of proteolytic machines unveiled by the synergy between cryo-EM and solution NMR spectroscopy
Bibliographic record
Abstract
Mechanistic studies of biomolecular machines involved in intracellular protein degradation-such as the caseinolytic protease P, ATPases associated with diverse cellular activities (AAA+) motors, and the high-temperature requirement A family of enzymes-are of great interest as they are implicated in a host of human diseases. The function of these systems is dependent on both their fine-tuned three-dimensional structure and the conformational dynamics that modulate this structure. Their large sizes, inherent conformational plasticity, and oligomeric heterogeneity dictate that their mechanism of action cannot be deciphered by any one method. Synergistic application of methyl-transverse relaxation optimized spectroscopy (methyl-TROSY), nuclear magnetic resonance (NMR), and single-particle electron cryomicroscopy (cryo-EM) has uniquely positioned researchers to tackle the outstanding questions in this area of structural biology. Cryo-EM enables structural characterization and modeling of the large and conformationally heterogeneous complexes involved in protein degradation, while methyl-TROSY NMR enables monitoring structural transitions and conformational dynamics of these systems in response to various stimuli in solution at atomic resolution. This review highlights how combining these two approaches offers a distinct and powerful means to unravel allosteric pathways within complex, multipartite biomolecular machines.
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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) | 0.001 | 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".