- Fold
- Seven transmembrane helices; multi-pass plasma-membrane receptor; non-enzyme.
- Orthosteric Pocket
- High-priority hypothesis (AstraBIND confidence 0.718). A residue-level pocket in the class A helical bundle (TM5, TM6, TM7) — a concrete starting point for docking and mutagenesis, not a claim of proven ligandability. No validated ligand.
- Structural Anchors
- Conserved TM3–ECL2 disulfide C95–C171; N-glycosylation at N3 (UniProt).
- Flexible Regions
- Elevated predicted disorder — disordered N-terminus (1–13), long intracellular loop (209–281) and C-tail (353–373) — 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. GPR27 remains dark: an IDG Tbio class A GPCR with no experimental structure in the PDB, no confirmed endogenous ligand, and a thin primary literature. It is one of the three SREB receptors — super-conserved receptors expressed in brain — highly conserved across vertebrates, a conservation that usually marks a function under selection, yet the receptor stays orphan; UniProt can place it only tentatively, as a possible amine-like receptor. Interest is nonetheless real: a pancreatic β-cell siRNA screen implicated GPR27 in insulin production, and later work tied it to glucose homeostasis.
That combination — genuine interest, near-zero structural information — is exactly where prediction earns its keep: everything below is computed from the canonical 375-residue sequence with Orbion's Astra suite, with no experimental GPR27 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: 24–44; 56–76; 98–118; 140–160; 182–202; 286–306; 321–341. |
The Predicted Pocket
The Predicted Orthosteric Pocket
A residue-level orthosteric hypothesis from AstraBIND (confidence 0.718). As a positive control, AstraBIND places it at the canonical class A orthosteric site — a Ballesteros–Weinstein 3.32 anchor hit, the same pocket the detector recovers on class A GPCRs with solved structures — so this is a like-for-like prediction, not an extrapolation into empty space. Still a computational hypothesis: no validated ligand, and not a proven druggable site.
Site: Class A helical bundle (extracellular-facing cavity)
Post-Translational & Structural Features
Specific, Testable Residues
- Disulfide bond C95–C171. Annotated in UniProt (rule-based); the conserved class A TM3–ECL2 bridge that caps the orthosteric pocket — a fold sanity-check and a Cys→Ala mutagenesis handle.
- N-glycosylation at position 3 — on the short extracellular N-terminus (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 |
|---|---|---|
| Orthosteric-Pocket Residues (TM5, TM6, TM7) | Alanine scan + docking / fragment screen at the predicted site | Ligand binding or SAR at the predicted pocket |
| Disulfide C95–C171 | Cys→Ala mutagenesis (C95A, C171A) | Expression / fold loss — fold-integrity check |
| Disordered ICL3 (209–281) and C-Tail (353–373) | Fusion-partner insertion or terminal truncation | Expression / thermostability for structural work |
| Predicted Amine-Like Receptor Class | Surrogate-agonist / β-arrestin recruitment assay | Confirm coupling and functional annotation |
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 hypothesis, not a proven druggable site or a validated binder.
- Thin, model-organism biology. GPR27 has no confirmed endogenous ligand; the metabolic case rests largely on a pancreatic β-cell siRNA screen and zebrafish knockouts, and the amine-like classification is a sequence-based guess. Treat both the pocket and the function as hypotheses.
All predictions were generated with Orbion's Astra suite from the canonical GPR27 sequence (UniProt Q9NS67), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry Q9NS67 (GPR27, human). uniprot.org.
- [2]Pharos (Illuminating the Druggable Genome). GPR27 target record — Tbio. pharos.nih.gov.
- [3]Ku GM et al. An siRNA screen in pancreatic beta cells reveals a role for Gpr27 in insulin production. (2012). https://doi.org/10.1371/journal.pgen.1002449
- [4]Dupuis N et al. Activation of the Orphan G Protein-Coupled Receptor GPR27 by Surrogate Ligands Promotes β-Arrestin 2 Recruitment. (2017). https://doi.org/10.1124/mol.116.107714
- [5]Nath AK et al. Genetic deletion of gpr27 alters acylcarnitine metabolism, insulin sensitivity, and glucose homeostasis in zebrafish. (2020). https://doi.org/10.1096/fj.201901466r