- Fold
- A single-domain α/β-hydrolase (soluble fold), membrane-anchored in vivo via N-terminal palmitoylation; see the domain map and disorder profile.
- Active-Site Region
- AstraBIND's highest-confidence call on this target (0.903) — a residue-level active-site hypothesis clustered around the catalytic triad. A concrete starting point for docking and covalent-probe design; no validated inhibitor.
- Flexible Regions
- Elevated predicted disorder across the N-terminus (1–55) — the natural truncation boundary for a crystallisable construct.
- Clean Signal
- No amyloidogenic segments predicted.
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
Most tractable enzyme families have been structurally explored. ABHD17A has not: an IDG Tbio α/β-hydrolase with no experimental structure in the PDB and only a handful of functional studies. UniProt records that it hydrolyses fatty acids from S-acylated cysteines and depalmitoylates both NRAS and the postsynaptic scaffold PSD-95 — placing it squarely in the RAS palmitoylation cycle that many tumour cells depend on. But the fold, the catalytic machinery and the druggable surface all have to be inferred.
That combination — a credible oncology rationale with near-zero structural information — is where prediction earns its keep: everything below is computed from the canonical 310-residue sequence, with no experimental ABHD17A structure used as input.
Architecture & Topology
How the Sequence Is Organised
| Element | Residues | Note |
|---|---|---|
| Chain | 1–310 | Single-chain; see disorder profile and pocket below. |
The Predicted Pocket
The Predicted Active-Site Region
A residue-level active-site hypothesis from AstraBIND. As a positive control, the predicted residues recover the UniProt-annotated catalytic triad (190, 255, 284) — the detector lands on the known active site, not an arbitrary surface. Still a computational hypothesis for prioritising experiments, not a validated inhibitor or a proven druggable site.
Site: Predicted substrate / cofactor-facing residues
Post-Translational & Structural Features
Specific, Testable Residues
- Catalytic triad (charge-relay system). The serine-hydrolase triad at positions 190, 255 and 284 — the active site that carries out depalmitoylation, and the obvious mutagenesis handle (a Ser190→Ala mutant is the natural catalytic-dead control).
- No amyloidogenic segments predicted. The ordered core is a clean expression target once the disordered N-terminus is trimmed.
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 |
|---|---|---|
| Catalytic Triad (190 / 255 / 284) | Ser190→Ala point mutant + protein-depalmitoylation assay | Loss of thioesterase activity — confirms the predicted active site |
| Predicted Active-Site Pocket | Covalent-fragment / activity-based-probe screen at the predicted site | Engagement or inhibition — a starting point for chemical tools |
| Disordered N-Terminus (1–55) | N-terminal truncation | Improved expression / crystallisability |
Scope & Limitations
What This Is — and Isn't
- Prediction, not experiment. These are computational hypotheses to prioritise experiments — not a structure or an assay. Nothing here is wet-lab validated.
- The pocket is predicted; the ligand is not named. AstraBIND is retrieval-based; the honest output is a residue-level active-site hypothesis, not a proven druggable site or a validated inhibitor.
- Thin biology. ABHD17A's role is inferred largely from its depalmitoylation of N-Ras and PSD-95 and a small number of reports; its selectivity, regulation and contribution to disease remain sparsely characterised. Treat the oncology rationale as a hypothesis.
All predictions were generated with Orbion's Astra suite from the canonical ABHD17A sequence (UniProt Q96GS6), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry Q96GS6 (ABHD17A, human). uniprot.org.
- [2]Pharos (Illuminating the Druggable Genome). ABHD17A target record — Tbio. pharos.nih.gov.
- [3]McClafferty H et al. Site-specific deacylation by ABHD17a controls BK channel splice variant activity. (2020). https://doi.org/10.1074/jbc.ra120.015349
- [4]Lin DT, Conibear E. ABHD17 proteins are novel protein depalmitoylases that regulate N-Ras palmitate turnover and subcellular localization. (2015). https://doi.org/10.7554/elife.11306
- [5]Shi X et al. The Unconventional Role of ABHD17A in Increasing the S-Palmitoylation and Antiviral Activity of IFITM1 by Downregulating ABHD16A. (2025). https://doi.org/10.3390/biom15070992