- Fold
- Ten predicted transmembrane helices in the SLC35 (nucleotide-sugar-transporter-like) fold; multi-pass membrane protein; non-enzyme.
- Substrate Cavity
- A residue-level substrate-cavity hypothesis from AstraBIND (confidence 0.828, HIGH), unclassified — a starting point for docking and cavity mutagenesis, not a validated ligand.
- Flexible Regions
- Elevated predicted disorder at the cytosolic N-terminus (1–29) and C-terminal tail (341–373) — natural truncation boundaries for construct design.
- Clean Signal
- One aggregation-prone segment flagged (AstraUNFOLD amyloid max 0.511) — 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. SLC35F2 has not: an IDG Tbio solute carrier with no experimental structure in the PDB and, until recently, no assigned substrate. That substrate is now identified — SLC35F2 is a high-affinity plasma-membrane importer of queuine and queuosine, bacterially derived micronutrients from diet and the gut microbiome that are incorporated at the tRNA wobble position to support efficient translation. Its oncology interest is better established than its structure: SLC35F2 is the route by which the anticancer agent YM155 (sepantronium) enters cells to do its DNA damage, it is over-expressed in non-small-cell lung cancer — with transcript levels modestly tracking pathological staging — and its degradation confers YM155 resistance.
The gap is structural, not biological: everything below is computed from the canonical 374-residue sequence with Orbion's Astra suite, with no experimental SLC35F2 structure used as input. For a transporter with real oncology traction and no solved fold, prediction is the place to start.
Architecture & Topology
How the Sequence Is Organised
| Element | Residues | Note |
|---|---|---|
| Transmembrane Helices | 10 predicted | Boundaries: 39–59; 73–93; 108–125; 136–156; 165–185; 195–215; 227–247; 263–283; 291–311; 314–334. |
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
- Aggregation-prone segment flagged (AstraUNFOLD amyloid max 0.511) — 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 (TM2, TM7, TM8) | Cavity-lining alanine scan + queuosine or YM155 uptake assay | Loss of transport at the predicted site |
| Disordered N-Terminus and C-Tail (1–29, 341–373) | Terminal truncation or fusion-partner insertion | Improved expression / thermostability for structural work |
| Predicted SLC35 Transporter Class | Queuine/queuosine or YM155 uptake in a defined cell system | Confirm transport function and 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 oncology case is drug uptake, not target validation. SLC35F2's cancer relevance rests on importing the drug YM155 and on over-expression that tracks with lung-cancer staging — it is a drug-uptake route and a candidate biomarker, not a validated therapeutic target. The cavity hypothesis names residues to test, and makes no claim that inhibiting SLC35F2 is beneficial.
All predictions were generated with Orbion's Astra suite from the canonical SLC35F2 sequence (UniProt Q8IXU6), using AlphaFold-derived structural features. Reported values are model outputs; model internals are out of scope.
References
- [1]UniProt Consortium. UniProtKB entry Q8IXU6 (SLC35F2, human). uniprot.org.
- [2]Pharos (Illuminating the Druggable Genome). SLC35F2 target record — Tbio. pharos.nih.gov.
- [3]Winter GE et al. The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity. (2014). https://doi.org/10.1038/nchembio.1590
- [4]Bu L et al. Highly expressed SLC35F2 in non-small cell lung cancer is associated with pathological staging. (2011). https://doi.org/10.3892/mmr.2011.572
- [5]Chandrasekaran AP et al. USP32 confers cancer cell resistance to YM155 via promoting ER-associated degradation of solute carrier protein SLC35F2. (2021). https://doi.org/10.7150/thno.63806