- Fold
- Seven transmembrane helices; multi-pass plasma-membrane receptor; non-enzyme.
- Binding Pocket
- Predicted binding pocket (AstraBIND confidence 0.767, high). A residue-level cavity in the class A helical bundle (TM6, TM7) — a starting point for docking and mutagenesis; unclassified, with no validated ligand.
- Structural Anchors
- N-glycosylation on the extracellular N-terminus — predicted sequons at N4, N11, N17 and N27, experimentally confirmed (Wang 2020).
- Flexible Regions
- Elevated predicted disorder — disordered N-terminus (1–31) and an unusually long cytoplasmic C-tail (346–511) — 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 tractable receptor families have been structurally explored. GPR176 remains dark: an IDG Tbio class A GPCR with no experimental structure in the PDB and no confirmed ligand. Its defining feature is constitutive: it couples to the G(z) subclass and, without any agonist, holds cAMP production repressed — a basal tone reported to help set the pace of circadian behaviour in the brain's master clock. More recent work links it to cancer progression, giving a second, independent reason to characterise it.
That combination — genuine interest, near-zero structural information — is exactly where prediction earns its keep: everything below is computed from the canonical 515-residue sequence with Orbion's Astra suite, with no experimental GPR176 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 |
|---|---|---|
| Transmembrane Helices | 7 predicted | Boundaries: 43–63; 83–103; 119–139; 161–181; 208–228; 268–288; 300–320. |
The Predicted Pocket
A Predicted Binding Pocket
For this genuine orphan, AstraBIND has no ligand-bound relative to retrieve from — so these residues are a structure-based cavity prediction, not a retrieval-grounded pocket, and the score reflects cavity geometry rather than a known binding site. Treat them as an exploratory starting point for mutagenesis only; the topology, disorder and modification maps above are the higher-confidence outputs for this target. No validated ligand; not a proven druggable site.
Site: Class A helical bundle (extracellular-facing cavity)
Post-Translational & Structural Features
Specific, Testable Residues
- N-glycosylation at position 4, 11, 17, 27 — a cluster on the extracellular N-terminus whose N-linked glycosylation has been functionally characterised for GPR176 (UniProt).
- No amyloidogenic segments predicted. A clean aggregation profile across the sequence — one fewer liability for construct design.
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 |
|---|---|---|
| Binding-Pocket Residues (TM6, TM7) | Alanine scan + docking / fragment screen at the predicted pocket | Binding or SAR at the predicted site |
| N-Glycosylation Cluster (N4, N11, N17, N27) | N→Q mutagenesis of the N-terminal sites | Trafficking / surface-expression shift |
| Disordered N-Term (1–31) and Long C-Tail (346–511) | Terminal truncation or fusion-partner insertion | Expression / thermostability for structural work |
| Constitutive G(z) Signalling | cAMP assay for agonist-independent basal activity | Confirm G(z) coupling and basal cAMP repression |
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 and here returns an unclassified cavity — a residue-level hypothesis, not a proven druggable site or a validated binder.
- Biology from model systems, and maybe no ligand to find. GPR176's circadian role rests on mouse SCN studies and its cancer link on recent tumour work; because it signals constitutively through G(z) with no known agonist, there may be no classical orthosteric ligand at all. Treat both the pocket and the therapeutic case as hypotheses.
All predictions were generated with Orbion's Astra suite from the canonical GPR176 sequence (UniProt Q14439), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry Q14439 (GPR176, human). uniprot.org.
- [2]Pharos (Illuminating the Druggable Genome). GPR176 target record — Tbio. pharos.nih.gov.
- [3]Doi M et al. Gpr176 is a Gz-linked orphan G-protein-coupled receptor that sets the pace of circadian behaviour. (2016). https://doi.org/10.1038/ncomms10583
- [4]Tang J et al. GPR176 Promotes Cancer Progression by Interacting with G Protein GNAS to Restrain Cell Mitophagy in Colorectal Cancer. (2023). https://doi.org/10.1002/advs.202205627
- [5]Wang T et al. Identification and functional characterisation of N-linked glycosylation of the orphan G protein-coupled receptor Gpr176. (2020). https://doi.org/10.1038/s41598-020-61370-y