- Predicted Function
- Hydrolase enzyme — EC 3, p=1.00. From sequence alone Astra recovers the serine-hydrolase identity with near-certainty (enzyme, p=0.99).
- Active Site
- Pocket lands on the catalytic triad. A HIGH-confidence pocket (0.90) whose residues include the annotated charge-relay triad Ser119, Asp179, His206 — the predicted active site coincides with the catalytic machinery.
- Fold
- Soluble; a small (227 aa) α/β-hydrolase, predominantly ordered (one short disordered insert, ~44–68); no membrane or amyloid signal.
- Modifications
- Predicted redox-type marks (glutathionylation, S-nitrosylation) plus phosphorylation — candidate regulation of a cysteine-adjacent active site.
- Open Questions
- No experimental structure; no physiological substrate; tumour-suppressor role unproven.
Model-reported confidence for the headline calls (amber = the load-bearing prediction the rest of the profile builds on). These are model-estimated probabilities that rank and gate each call — not calibrated rates of experimental success.
The Gap
Why This Target Is Still Dark
OVCA2 was discovered by position, not by function. It sits in the 17p13.3 minimal region of allelic loss in ovarian cancer, identified alongside OVCA1 as a candidate tumour-suppressor gene, with its transcript reduced or undetectable in the large majority of ovarian tumours and cell lines. Later work showed OVCA2 is a genuine serine hydrolase — it cleaves long-chain p-nitrophenyl alkyl esters — and is degraded during retinoid-induced apoptosis. But it has no experimental structure in the PDB, no known physiological substrate, and its tumour-suppressor role is unproven (later analyses favour its neighbour OVCA1/DPH1). It remains understudied (IDG Tbio).
That combination — a real enzyme with no structure and no substrate — is exactly where prediction earns its keep: everything below is computed from the canonical 227-residue sequence and derived structural predictions, with no experimental OVCA2 structure used as input. There is nothing to look up.
Architecture & Topology
How the Sequence Is Organised
| Element | Residues | Note |
|---|---|---|
| α/β-hydrolase fold | 5–222 | Small α/β-hydrolase core spanning nearly the whole chain; predominantly ordered. |
| Disordered insert | 44–68 | One short disordered insert within the fold. |
| Catalytic triad | Ser119, Asp179, His206 | Serine-hydrolase charge-relay system; all three fall inside the predicted pocket. |
The Predicted Pocket
The Predicted Active Site
A HIGH-confidence pocket (0.90) whose residues bracket the catalytic triad Ser119, Asp179 and His206. The predicted active site is not an extrapolation into empty space: it lands on the residues UniProt annotates as the charge-relay system. As a control, the same pocket detection recovers the known catalytic/ligand sites on hydrolases whose structures are solved.
Site: Serine-hydrolase active site — the Ser–His–Asp charge-relay triad
Post-Translational & Structural Features
Specific, Testable Residues
- Glutathionylation and S-nitrosylation. Predicted cysteine-directed redox modifications — a plausible regulatory layer for a hydrolase, and consistent with OVCA2's reported turnover during retinoid-induced (oxidative-stress-associated) apoptosis.
- Phosphorylation. A small set of predicted phosphosites — candidate control points for activity or stability.
- No membrane or amyloid signal. A clean, soluble, compact enzyme — a viable target for structural work.
Recommended Experimental Follow-Up
An Orphan Sequence, Turned Into a Ranked Plan
Each prediction is paired with the experiment that would test it and the readout to watch for.
| Prediction | Experiment | Readout |
|---|---|---|
| Serine-hydrolase / esterase class | Activity-based protein profiling (fluorophosphonate probe) | Confirm an active serine hydrolase |
| Catalytic triad Ser119 / Asp179 / His206 | S119A, D179A, H206A active-site mutants | Loss of activity — validates the predicted triad |
| Predicted pocket residues | Substrate-panel / fragment screen at the pocket | Substrate preference; a route to a physiological substrate |
| Redox modifications (Cys) | Glutathionylation / SNO detection ± oxidative stress | Redox regulation of activity |
| Retinoid-induced degradation | Pocket-/triad-mutant stability under RA | Whether catalysis couples to turnover |
Scope & Limitations
What This Is — and Isn't
- Prediction, not experiment. These are computational hypotheses to prioritise experiments — not a substitute for a structure or an assay. No result here has been validated in the wet lab.
- Triad numbering. We use the UniProt charge-relay annotation (Ser119/Asp179/His206); mutagenesis in the FSH1-comparison study confirms the catalytic serine and histidine but numbers the nucleophile Ser117 — a two-residue offset to note when designing mutants.
- Biology caveats. OVCA2's tumour-suppressor role is unproven (later work favours the neighbouring gene OVCA1/DPH1), and no physiological substrate is known. Treat the disease case as a hypothesis.
All predictions were generated with Orbion's Astra suite from the canonical OVCA2 sequence (UniProt Q8WZ82), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry Q8WZ82 (OVCA2, human). uniprot.org.
- [2]Pharos / Illuminating the Druggable Genome. OVCA2 target record — Tbio. pharos.nih.gov/targets/Q8WZ82.
- [3]Schultz D.C., Vanderveer L., Berman D.B., Hamilton T.C., Wong A.J., Godwin A.K. Identification of two candidate tumor suppressor genes on chromosome 17p13.3. Cancer Res. 56(9), 1997–2002 (1996). https://pubmed.ncbi.nlm.nih.gov/8616839/
- [4]Bun J.S., Slack M.D., Schemenauer D.E., Johnson R.J. Comparative analysis of the human serine hydrolase OVCA2 to the model serine hydrolase homolog FSH1 from S. cerevisiae. PLoS ONE 15(3), e0230166 (2020). https://doi.org/10.1371/journal.pone.0230166
- [5]Prowse A.H., Vanderveer L., Milling S.W.F., et al. OVCA2 is downregulated and degraded during retinoid-induced apoptosis. Int. J. Cancer 99(2), 185–192 (2002). https://doi.org/10.1002/ijc.10334
- [6]Bozkurt Ç., Vasilyeva A., Goteti A. AstraROLE2 & AstraSUIT2: Multi-Task Annotation Models for Functional Profiling of Proteins. bioRxiv 2025.06.21.660734 (2025). https://doi.org/10.1101/2025.06.21.660734
- [7]Bozkurt Ç., Vasilyeva A., Goteti A. AstraPTM2: A Context-Aware Transformer for Broad-Spectrum PTM Prediction. bioRxiv 2025.10.03.680341 (2025). https://doi.org/10.1101/2025.10.03.680341
- [8]Goteti A., Vasilyeva A., Bozkurt Ç. AstraBIND: Graph Attention Network for Predicting Ligand Binding Sites. bioRxiv 2025.11.10.687555 (2025). https://doi.org/10.1101/2025.11.10.687555