Abstract 1205 The mitochondrial ClpP protease: from basic principles to drug discovery
Bibliographic record
Abstract
Mitochondrial matrix ClpP is a serine protease that forms a tetradecameric cylindrical structure. ClpP acts as a complex with the hexameric ATPase ClpX to form the ClpXP ATP-dependent protease. ClpXP is responsible for mitochondrial protein quality control through specific degradation of proteins involved in several metabolic processes. Furthermore, ClpP overexpression is required in many cancer cells to eliminate ROS-damaged proteins and to sustain oncogenesis. Targeting ClpP to dysregulate its function using small molecule agonists is a recent strategy in cancer therapy. Here, we describe the mechanism of function of ClpXP and the development of novel compounds that dysregulate the activity of the protease. Using X-ray crystallography, we found that these compounds bind at surface hydrophobic pockets of ClpP preventing ClpX interaction. N-terminome profiling of cancer cells upon treatment with one of these compounds revealed the global proteomic changes that arise and identified the structural motifs preferred for protein cleavage by compound-activated ClpP. Together, our studies provide the structural and molecular bases by which dysregulated ClpP affects cancer cell viability and proliferation. Canadian Institutes of Health Research (PJT-173345) Canadian Cancer Society Innovation Grant (Grant #706282)
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
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".