- Fold
- Seven transmembrane helices; multi-pass plasma-membrane receptor; non-enzyme; likely monomeric.
- Orthosteric Pocket
- High-priority hypothesis. A residue-level pocket at the canonical class A orthosteric site (TM3, ECL2, TM5, TM6, TM7) — a concrete starting point for docking, mutagenesis and ligand-screen design. No validated small-molecule ligand; the CARTp pairing is contested in human systems.
- Structural Anchors
- Conserved TM3–ECL2 disulfide (C94–C173); C-terminal S-palmitoylation (C316); N-terminal N-glycosylation (N7).
- Flexible Regions
- Short disordered N-terminus (1–22), disordered ICL3 (211–231), disordered C-tail (301–338) — the natural truncation boundaries for construct design.
- 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 therapeutically tractable receptor families have been structurally explored. GPR160 remains largely dark: an IDG Tdark class A GPCR with no experimental structure in the PDB, no confirmed endogenous ligand, and a thin primary literature. The proposed CART-peptide pairing is disputed in human cells, so even its pharmacology is unsettled. Yet interest is real: GPR160 is over-expressed across prostate-cancer cohorts and has been tied to neuropathic-pain signalling.
That combination — high interest, near-zero structural information — is exactly where prediction earns its keep: everything below is computed from the canonical 338-residue sequence and derived structural predictions, with no experimental GPR160 structure or validated ligand used as input. For a genuine orphan, there is nothing to look up.
Architecture & Topology
How the Sequence Is Organised
| Element | Residues | Note |
|---|---|---|
| N-terminus | 1–23 | Short, extracellular; disordered 1–22; glycosylated at N7. |
| TM1–TM7 | 24–294 | Helices 24–44, 58–79, 97–118, 140–157, 183–204, 241–264, 273–294. |
| ECL2 | 158–182 | Carries C173 of the conserved disulfide; contributes to the pocket. |
| ICL3 | 205–240 | Disordered core 211–231; clustered phospho-sites (putative GRK/PKC). |
| C-terminus | 295–338 | Disordered 301–338; palmitoylation anchor at C316. |
The Predicted Pocket
The Predicted Orthosteric Pocket
A high-priority, residue-level hypothesis — a concrete starting point for docking, mutagenesis and ligand-screen design, not a claim of proven ligandability. GPR160 has no validated small-molecule ligand; the CARTp pairing remains contested in human systems.
Site: Canonical class A orthosteric site (TM3, ECL2, TM5, TM6, TM7)
Post-Translational & Structural Features
Specific, Testable Residues
- Conserved disulfide C94–C173. Links the extracellular tip of TM3 to ECL2 — the bridge that caps the orthosteric pocket in class A GPCRs. A structural sanity check and a mutagenesis handle.
- S-palmitoylation at C316. In the C-terminal tail, consistent with a membrane-anchored helix 8 that forms a fourth intracellular loop — relevant to trafficking and G-protein coupling.
- N-glycosylation at N7. On the short extracellular N-terminus.
- Phosphorylation clusters in ICL3 (222–231) and the C-tail (333) — the expected footprint of GRK/PKC regulation and a starting point for signalling studies.
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 |
|---|---|---|
| Orthosteric-pocket residues (TM3, TM6, TM7) | Alanine scan + docking / fragment screen at the predicted site | Ligand binding or SAR at the predicted pocket |
| Conserved disulfide C94–C173 | Cys→Ala mutagenesis (C94A, C173A) | Expression / fold loss — fold-integrity check |
| S-palmitoylation at C316 | C316A point mutant | Trafficking / signalling shift |
| Disordered ICL3 (211–231) | Fusion-partner insertion or loop deletion | Expression / stability improvement |
| Disordered C-tail (301–338) | C-terminal truncation | Improved amenability to cryo-EM / crystallography |
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.
- The pocket is predicted; the ligand is not named. For a genuine orphan the honest output is a residue-level pocket hypothesis, not a drug. We make no claim about ligandability or which chemotype binds.
- Biology caveats. The CART-peptide pairing for GPR160 is disputed in human systems, and the disease rationale rests on expression data. Treat the therapeutic case as a hypothesis.
All predictions were generated with Orbion's Astra suite from the canonical GPR160 sequence (UniProt Q9UJ42), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry Q9UJ42 (GPR160, human). uniprot.org.
- [2]Pharos (Illuminating the Druggable Genome). GPR160 target record — Tdark. pharos.nih.gov.
- [3]Ye C., Zhou Q., Lin S., et al. High expression of GPR160 in prostate cancer is unrelated to CARTp-mediated signaling pathways. Acta Pharm. Sin. B 14(3), 1467–1471 (2024). https://doi.org/10.1016/j.apsb.2023.11.025
- [4]Guo W., Zhang J., Zhou Y., et al. GPR160 is a potential biomarker associated with prostate cancer. Signal Transduct. Target. Ther. 6 (2021). https://doi.org/10.1038/s41392-021-00583-7