- Fold
- Twelve predicted transmembrane helices, the SLC22 organic-ion-transporter fold; multi-pass plasma-membrane protein; non-enzyme.
- Substrate Cavity
- A residue-level substrate-cavity hypothesis from AstraBIND (confidence 0.852, HIGH), unclassified — a starting point for docking and cavity mutagenesis, not a validated ligand.
- Structural Anchors
- Predicted N-glycosylation at N58, N63, N80 and N106 (UniProt), clustered on the large extracellular loop between TM1 and TM2.
- Flexible Regions
- Elevated predicted disorder in the extracellular loop (56–76) and the cytosolic C-tail (501–546) — natural truncation boundaries for construct design.
- Clean Signal
- One aggregation-prone segment flagged (AstraUNFOLD amyloid max 0.513) — worth screening in construct design.
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 membrane-transporter families have been structurally explored. SLC22A15 — also called FLIPT1 — has not, and unusually little else about it has either: an IDG Tdark orphan of the SLC22 organic-ion transporter family, with no experimental structure in the PDB, no disease association, and no settled physiological substrate. Reported activities are broad and low-affinity — a zwitterion/cation carrier shown in vitro to move carnitine and acetylcarnitine, glycine betaine, diet-derived ergothioneine and carnosine, and, more weakly, thiamine — but even the transport mechanism (sodium symport versus sodium-modulated diffusion) is unresolved. It is dark in the fullest sense.
That is exactly where prediction earns its keep — not to declare a function, but to give the first structural handles on an orphan: everything below is computed from the canonical 547-residue sequence with Orbion's Astra suite, with no experimental SLC22A15 structure used as input. For a target this dark, there is nothing to look up.
Architecture & Topology
How the Sequence Is Organised
| Element | Residues | Note |
|---|---|---|
| Transmembrane Helices | 12 predicted | Boundaries: 22–42; 111–131; 141–161; 165–187; 201–221; 226–246; 303–323; 338–358; 368–388; 401–420; 433–453; 462–482. |
The Predicted Pocket
The Predicted Substrate Cavity
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: Predicted central translocation cavity
Post-Translational & Structural Features
Specific, Testable Residues
- N-glycosylation at position 58, 63, 80, 106 (UniProt) — clustered on the large extracellular loop between TM1 and TM2, the glycosylated face typical of SLC22 carriers and a handle for surface-expression assays.
- Aggregation-prone segment flagged (AstraUNFOLD amyloid max 0.513) — a predicted amyloidogenic stretch to screen out or engineer around in 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 |
|---|---|---|
| Substrate-Cavity Residues (TM7, TM8, TM10, TM11) | Cavity-lining alanine scan + organic-ion uptake assay (e.g. carnitine, ergothioneine) | Loss of transport at the predicted site |
| Disordered Loop and C-Tail (56–76, 501–546) | Loop / terminal truncation or fusion-partner insertion | Improved expression / thermostability for structural work |
| Predicted SLC22 Organic-Ion Transporter Class | Uptake panel across candidate zwitterions / cations in a defined system | Confirm transport function and rank substrate selectivity |
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.
- The biology is genuinely unresolved. SLC22A15 (FLIPT1) has no disease association and no agreed physiological substrate — reported cargoes are broad and low-affinity, and even its transport mechanism is unsettled. This profile offers structural starting points for an orphan, not a function; every claim here is computational and awaits a transport assay.
All predictions were generated with Orbion's Astra suite from the canonical SLC22A15 sequence (UniProt Q8IZD6), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry Q8IZD6 (SLC22A15, human). uniprot.org.
- [2]Pharos (Illuminating the Druggable Genome). SLC22A15 target record — Tdark. pharos.nih.gov.
- [3]Nigam SK. et al. The SLC22 Transporter Family: A Paradigm for the Impact of Drug Transporters on Metabolic Pathways, Signaling, and Disease. (2018). https://doi.org/10.1146/annurev-pharmtox-010617-052713
- [4]Alexander SP et al. The Concise Guide to PHARMACOLOGY 2013/14: transporters. (2013). https://doi.org/10.1111/bph.12450
- [5]Wu W et al. Remote communication through solute carriers and ATP binding cassette drug transporter pathways: an update on the remote sensing and signaling hypothesis. (2011). https://doi.org/10.1124/mol.110.070607