A In-solution Snapshot of SARS-COV-2 Main Protease Maturation Process and Inhibition
Bibliographic record
Abstract
Abstract Mpro is the main protease of SARS-CoV-2. Its dimeric form is responsible for cleavage of the viral polyprotein at 11 sites, including its own N- and C-termini. Mpro self-cleavage is called maturation, and it is crucial for enzyme dimerization and activity. Recently, we combined x-ray crystallography with biochemical characterization to depict key steps of the maturation process. A single mutant C145S version of Mpro linked to nsp4 cleavage sequence was introduced, allowing us to monitor enzyme shifts between oligomeric states in a human timescale. In here, we used C145S Mpro to study the structure and dynamics of N-terminal cleavage in solution. Native mass spectroscopy analysis showed that mixed oligomeric states are composed of cleaved and uncleaved particles, indicating that N-terminal processing is not critical to oligomerization. A 3.5 Å cryo-EM structure provides details of Mpro N-terminal cleavage in solution, and a glimpse in the dynamic of the active sites outside the constrains of crystal environment. We explored how different classes of inhibitors shift the balance between oligomeric states of Mpro. While non-covalent inhibitor MAT-POS-e194df51-1 prevents oligomerization, we discovered that the covalent inhibitor Nirmatrelvir induces the conversion of monomers into dimers, even with intact N-terminal. Our data indicates that the Mpro dimerization is triggered by the induced fit caused by the covalent linkage during substrate processing rather than the N-terminal processing.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
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".