- Fold
- Seven transmembrane helices; multi-pass plasma-membrane receptor; non-enzyme; likely monomeric.
- Orthosteric Pocket
- Testable hypothesis — medium confidence. A residue-level pocket at the canonical class A orthosteric site (TM3, ECL2, TM5, TM6, TM7); its nearest structural match is a cholesterol/lipid-type site. No confirmed endogenous ligand — only weak (~1 μM) synthetic tool compounds reported.
- Structural Anchors
- Conserved TM3–ECL2 disulfide (C93–C171). Strongly predicted; plus a C-terminal S-palmitoylation site (C356) and N-terminal N-glycosylation (N2).
- Flexible Regions
- A large disordered ICL3 (193–273), a short disordered N-terminus (1–10) and C-tail (356–370) — ~30% disordered overall.
- 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
GPR85 (SREB2) is a paradox. It is the most evolutionarily conserved GPCR in vertebrates — 100% identical in amino-acid sequence across human, rat and mouse — yet it remains a class A orphan with no confirmed endogenous ligand, no experimental structure in the PDB, and only a thin literature (understudied; IDG Tbio). Its biology is CNS-focused: mild over-expression reduces brain size and produces schizophrenia-endophenotype behaviours in mice, and the receptor negatively regulates adult hippocampal neurogenesis. The only ligands reported to date are weak (~1 μM) synthetic tool compounds.
That combination — high interest, near-zero structural information — is exactly where prediction earns its keep: everything below is computed from the canonical 370-residue sequence and derived structural predictions, with no experimental GPR85 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 | 1–20 | Short, extracellular; disordered 1–10; glycosylated at N2. |
| TM1–TM7 | see figure | 21–43, 59–79, 93–116, 139–161, 181–200, 288–310, 320–339. |
| ECL2 | 162–180 | Carries C171 of the conserved disulfide; contributes to the pocket. |
| ICL3 | 201–287 | Large disordered core (193–273); clustered phospho-sites (putative GRK/PKC). |
| C-terminus | 340–370 | Disordered 356–370; palmitoylation anchor at C356. |
The Predicted Pocket
The Predicted Orthosteric Pocket
A testable, residue-level hypothesis (medium confidence). The nearest structural match is a cholesterol/lipid-type site, so treat this as a lipid-facing cavity to probe rather than a proven druggable pocket. GPR85 has no confirmed endogenous ligand; only weak (~1 μM) synthetic tool compounds have been reported.
Site: Canonical class A orthosteric site (TM3, ECL2, TM5, TM6, TM7)
Post-Translational & Structural Features
Specific, Testable Residues
- Conserved disulfide C93–C171 (strongly predicted). Links the extracellular tip of TM3 to ECL2 — the canonical class A bridge that caps the orthosteric pocket. A high-confidence structural sanity check and mutagenesis handle.
- S-palmitoylation at C356. 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 N2. On the short extracellular N-terminus.
- Phosphorylation clusters in the disordered ICL3 (224–265) and the C-tail (341–366) — 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 C93–C171 | Cys→Ala mutagenesis (C93A, C171A) | Expression / fold loss — fold-integrity check |
| S-palmitoylation at C356 | C356A point mutant | Trafficking / signalling shift |
| Large disordered ICL3 (193–273) | Fusion-partner insertion or loop deletion | Expression / stability improvement |
| Weak synthetic tool compounds | Structure-guided SAR at the predicted pocket | Improved potency / selectivity |
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. GPR85's phenotypes come from mouse over-expression / knockout models; the endogenous ligand is unknown and reported synthetic ligands are weak. And the pocket here is a medium-confidence, lipid-adjacent call — treat the therapeutic case as a hypothesis.
All predictions were generated with Orbion's Astra suite from the canonical GPR85 sequence (UniProt P60893), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry P60893 (GPR85, human). uniprot.org.
- [2]Pharos / Illuminating the Druggable Genome. GPR85 target record — Tbio. pharos.nih.gov/targets/P60893.
- [3]Matsumoto M., Saito T., Takasaki J., et al. An evolutionarily conserved G-protein coupled receptor family, SREB, expressed in the central nervous system. Biochem. Biophys. Res. Commun. 272(2), 576–582 (2000). doi:10.1006/bbrc.2000.2829.
- [4]Matsumoto M., Straub R.E., Marenco S., et al. The evolutionarily conserved G protein-coupled receptor SREB2/GPR85 influences brain size, behavior, and vulnerability to schizophrenia. Proc. Natl. Acad. Sci. USA 105(16), 6133–6138 (2008). doi:10.1073/pnas.0710717105.
- [5]Chen Q., Kogan J.H., Gross A.K., et al. SREB2/GPR85, a schizophrenia risk factor, negatively regulates hippocampal adult neurogenesis and neurogenesis-dependent learning and memory. Eur. J. Neurosci. 36(5), 2597–2608 (2012). doi:10.1111/j.1460-9568.2012.08180.x.
- [6]Sakai A., Yasui T., Watanave M., et al. Development of novel potent ligands for GPR85, an orphan G protein-coupled receptor expressed in the brain. Genes Cells 27(5), 345–355 (2022). doi:10.1111/gtc.12931.