- Predicted Function
- Hydrolase enzyme — EC 3, p=0.99. Astra confirms the metallophosphoesterase identity (EC 3.6.1.16 / 3.6.1.53) from sequence alone.
- Active Site
- Pocket lands on the di-metal centre. A HIGH-confidence pocket (0.89), typed as a metal (Zn/Mn) site, whose residues include the homology-inferred catalytic set (Gln27, Asn110, His111 …).
- Fold
- Soluble, compact (342 aa) calcineurin-like metallophosphoesterase; predominantly ordered (~6% disorder); no membrane or amyloid signal.
- Substrates
- Hydrolyses ADP-ribose, cyclic ADP-ribose and CDP-alcohols — second messengers linked to TRPM2 / immune signalling.
- Open Question
- The human active-site geometry has never been solved — only inferred from a distant (zebrafish) homologue.
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
ADPRM is unusual among dark targets: its chemistry is known, but its human structure is not. It is a manganese-dependent hydrolase (ADPRibase-Mn family; a calcineurin-like metallophosphoesterase) that degrades ADP-ribose, cyclic ADP-ribose (cADPR) and CDP-alcohols — messengers tied to TRPM2, calcium and immune-cell signalling. Yet the human enzyme has no experimental structure in the PDB; its catalytic residues and di-metal centre are known only from substrate docking onto a homology model and from a distant zebrafish prototype (PDB 2NXF). It remains understudied (IDG Tbio), with no chemical probe.
That combination — a real enzyme whose human active site is unsolved — is exactly where prediction earns its keep: everything below is computed from the canonical 342-residue sequence and derived structural predictions, with no experimental human ADPRM structure used as input.
Architecture & Topology
How the Sequence Is Organised
| Element | Residues | Note |
|---|---|---|
| Metallophosphoesterase fold | 8–335 | Calcineurin-like metallophosphoesterase fold spanning essentially the whole chain; a compact single soluble domain. |
| Di-metal active site | 25, 27, 74, 77, 110–111, 211, 241, 278, 280 | Metal-coordinating / catalytic residues gathered from across the sequence into one centre; catalytic set Gln27, Asn110, His111 by homology. |
The Predicted Pocket
The Predicted Active Site
A HIGH-confidence pocket (0.89) typed as a metal (Zn/Mn) site whose residues include the homology-inferred catalytic set. The predicted active site is not an extrapolation into empty space: it lands on the residues expected to hold the di-metal centre. As a control, the same pocket detection recovers the known metal/ligand sites on metallophosphoesterases whose structures are solved (the family prototype, zebrafish 2NXF).
Site: Predicted metal (Zn/Mn) active site — the di-metal centre
Post-Translational & Structural Features
Specific, Testable Residues
- Predominantly ordered (~6% disorder), no amyloid. A clean, foldable enzyme — the whole chain is a viable target for structural work.
- N-terminal acetylation. A predicted co-translational modification consistent with a stable cytosolic protein.
- Compact single domain. No membrane signal; the catalytic metallophosphoesterase fold spans essentially the whole chain.
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 |
|---|---|---|
| Metallophosphoesterase / EC 3 class | ADP-ribose / cADPR hydrolysis assay (± Mn²⁺) | Confirm activity + metal dependence |
| Catalytic residues (Gln27, Asn110, His111) | Point mutants at the predicted set | Loss of activity — validates the site |
| Di-metal pocket | Metal-substitution / inhibitor soak | Metal identity; a starting point for inhibitors |
| cADPR-hydrolysis role | Activity on cADPR ± ADPRM in cells | Effect on cADPR / TRPM2 signalling |
| Soluble, orderable fold | Recombinant expression + crystallisation | The first human ADPRM structure |
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.
- Active site inferred, then predicted. The catalytic residues are themselves homology inferences (from docking onto a non-human prototype); Astra independently converges on the same site, but neither is an experimental determination.
- Biology caveats. The TRPM2 / immune-signalling role of ADPR / cADPR is established background biology; ADPRM's specific regulatory role in it is proposed, not proven.
All predictions were generated with Orbion's Astra suite from the canonical ADPRM sequence (UniProt Q3LIE5), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry Q3LIE5 (ADPRM, human) — EC 3.6.1.16 / 3.6.1.53. uniprot.org.
- [2]Pharos / Illuminating the Druggable Genome. ADPRM target record — Tbio. pharos.nih.gov/targets/Q3LIE5.
- [3]Canales J., Fernández A., Rodrigues J.R., et al. Mn²⁺-dependent ADP-ribose/CDP-alcohol pyrophosphatase: a novel metallophosphoesterase family preferentially expressed in rodent immune cells. Biochem. J. 413(1), 103–113 (2008). https://doi.org/10.1042/BJ20071471
- [4]Cabezas A., Ribeiro J.M., Rodrigues J.R., et al. Molecular bases of catalysis and ADP-ribose preference of human Mn²⁺-dependent ADP-ribose/CDP-alcohol diphosphatase. PLoS ONE 10(2), e0118680 (2015). https://doi.org/10.1371/journal.pone.0118680
- [5]Rodrigues J.R., Fernández A., Canales J., et al. Characterization of Danio rerio Mn²⁺-dependent ADP-ribose/CDP-alcohol diphosphatase, the structural prototype of the ADPRibase-Mn-like family (PDB 2NXF). PLoS ONE 7(7), e42249 (2012). https://doi.org/10.1371/journal.pone.0042249
- [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