- Fold
- Seven transmembrane helices; multi-pass plasma-membrane receptor; non-enzyme; likely monomeric — unusually large for a class A GPCR (731 aa).
- 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 known binder: a novel, structurally uncharacterised orphan pocket.
- Structural Anchors
- N-terminal N-glycosylation cluster (N6, N10, N20); a predicted disulfide-bond cysteine at C104 (TM3 tip); dense phosphorylation across the intracellular regions.
- Flexible Regions
- ~65% disordered by residue. Short disordered N-terminus (1–27), a large disordered ICL3 (219–303) and an unusually long disordered C-terminal region (368–731) — the dominant construct-design consideration.
- 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. GPR149 remains largely dark: an understudied (IDG Tbio) class A GPCR with no experimental structure in the PDB, no confirmed endogenous ligand, and an atypical microswitch architecture — a degenerate DRY motif and an unusually long C-terminus. Its best-established biology is in reproduction (Gpr149-null mice show increased fertility), and it has recently been repositioned as a neuro-metabolic target: knockouts partially resist diet-induced weight gain with improved insulin sensitivity, and the receptor negatively regulates myelination in the CNS.
That combination — high interest, near-zero structural information — is exactly where prediction earns its keep: everything below is computed from the canonical 731-residue sequence and derived structural predictions, with no experimental GPR149 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 | 1–35 | Short, extracellular; disordered 1–27; N-glycosylation cluster (N6, N10, N20). |
| TM1–TM7 | see figure | 36–57, 69–90, 108–128, 151–170, 191–211, 312–332, 346–362. |
| ECL2 | 171–190 | Contributes to the orthosteric pocket. |
| ICL3 | 212–311 | Large disordered insert (219–303); dense phospho-cluster (putative GRK/PKC). |
| C-terminus | 363–731 | Unusually long; largely disordered (368–731); extensive phosphorylation. |
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. GPR149 is a genuine orphan with no known binder — a novel, structurally uncharacterised pocket.
Site: Canonical class A orthosteric site (TM3, ECL2, TM5, TM6, TM7)
Post-Translational & Structural Features
Specific, Testable Residues
- N-glycosylation cluster (N6, N10, N20). Three sites on the short extracellular N-terminus — a surface-expression and trafficking handle.
- Extensive phosphorylation across the disordered ICL3 (219–303) and the long C-terminal region — an unusually large GRK/PKC-type regulatory surface, consistent with the atypical, extended C-terminus.
- Predicted disulfide-bond cysteine at C104 (extracellular tip of TM3); the ECL2 partner is not confidently resolved, so the canonical class A bridge is only partially supported here.
- No confident S-palmitoylation site — unlike many class A GPCRs, consistent with GPR149's atypical C-terminus.
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 |
|---|---|---|
| Long disordered C-terminal region (368–731) | C-terminal truncation for expression constructs | Improved amenability to cryo-EM / crystallography |
| Orthosteric-pocket residues (TM3, TM6, TM7) | Alanine scan + docking / fragment screen at the predicted site | Ligand binding or SAR at the predicted pocket |
| Large disordered ICL3 (219–303) | Fusion-partner insertion or loop deletion | Expression / stability improvement |
| N-glycosylation cluster (N6, N10, N20) | N→Q substitution | Surface expression / trafficking shift |
| Predicted disulfide cysteine C104 | Cys→Ala mutant | Expression / fold-integrity check |
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. GPR149's phenotypes derive from knockout-mouse models and its neuro-metabolic repositioning is recent; the endogenous ligand remains unknown. Treat the therapeutic case as a hypothesis.
All predictions were generated with Orbion's Astra suite from the canonical GPR149 sequence (UniProt Q86SP6), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry Q86SP6 (GPR149, human). uniprot.org.
- [2]Pharos / Illuminating the Druggable Genome. GPR149 target record — Tbio. pharos.nih.gov/targets/Q86SP6.
- [3]Edson M.A., Lin Y.-N., Matzuk M.M. Deletion of the novel oocyte-enriched gene, Gpr149, leads to increased fertility in mice. Endocrinology 151(1), 358–368 (2009). doi:10.1210/en.2009-0760.
- [4]Wyler S., Surbhi, Cao N., et al. Gpr149 is involved in energy homeostasis in the male mouse. PeerJ 12, e16739 (2024). doi:10.7717/peerj.16739.
- [5]Suo N., He B., Cui S., et al. The orphan G protein-coupled receptor GPR149 is a negative regulator of myelination and remyelination. Glia 70(10), 1992–2008 (2022). doi:10.1002/glia.24233.