IFNAR2 Target Deep Dive
Cytokine Receptor Modulation
Biological Context
Interferon Alpha/Beta Receptor 2 (IFNAR2) is one of the two receptor subunits that recognize Type I interferons (IFN-α, IFN-β). Type I interferons are powerful antivirals and immune regulators — cells secrete them in response to viral infection, and signaling through the IFNAR1/IFNAR2 complex triggers hundreds of interferon-stimulated genes.
Why it matters: Modulating this pathway matters in two opposite directions. In antiviral therapy (COVID-19, hepatitis C) you want to enhance or mimic IFN signaling. In autoimmune disease (lupus, interferonopathies) you want to block it — and a well-designed IFNAR2 binder that competes with natural IFN-α would do exactly that. IFNAR2’s interface with IFN-α is one of the most thoroughly characterized cytokine-receptor interactions in the literature, which makes it an unusually well-instrumented target for de novo design.
The Goal: Design a binder that occupies the IFN-α binding face of IFNAR2. Depending on orientation, your binder could block signaling (antagonist) or potentially trigger it (agonist).
Interactive Structure
The viewer below shows IFNAR2 (Chain B) in complex with IFN-α2 (Chain A) and IFNAR1 (Chain C) — the ternary signaling complex.
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Design Mission
Create a binder that targets the IFN-α binding interface of IFNAR2 — the surface that in 3SE3 is buried by chain A.
Target Specifications
| Feature | Detail |
|---|---|
| Target Name | IFNAR2 (Interferon alpha/beta receptor 2, extracellular domain) |
| PDB ID | 3SE3 |
| Target Chain | Chain B |
| Binder to mimic | Chain A (IFN-α2) |
| Published interface hotspots | P54, Y57, N58, S61–F64, N65, L66, S68, K70, D82, Y85, T86, Y89, Q90, L92, N93, E96, I116, L117, R120, K121, F123, Q124, T127 |
| Key “hot” residues | T44–K48 region, W100, I103, M148 are the classic energetic hot spots from alanine-scanning; in 3SE3 specifically, L66, Y89, R120, F123, Q124 dominate direct contacts with IFN-α2 |
These are every IFNAR2 residue with any heavy atom within 5 Å of IFN-α2 in 3SE3. The IFN/IFNAR2 interface has been mapped by mutagenesis for decades (Roisman 2001, Thomas 2011) — focus hotspots on the tryptophan/aromatic cluster (Y85, Y89, W100, F123) where single mutations substantially impact binding.
Strategy Tips
- Download PDB
3SE3. - Clean the structure: Keep Chain B only (IFNAR2). Remove IFN-α2 (A) and IFNAR1 (C).
- Define hotspots: For RFdiffusion / BindCraft, pass 4–6 of the “hot” residues (e.g.,
B66,B89,B120,B123,B124). The aromatic residues contribute outsized affinity; keep them in the hotspot set. - Consider orientation: IFN-α2 approaches IFNAR2 roughly along one face. Your binder must approach from the same general direction to avoid steric clash with IFNAR1 in a cellular context.
Reference
- Thomas, C. et al. (2011). Structural linkage between ligand discrimination and receptor activation by type I interferons. Cell 146, 621–632. doi:10.1016/j.cell.2011.06.048 — primary citation for 3SE3.
- Roisman, L.C. et al. (2001). Mutational analysis of the IFNAR2 binding site. PNAS 98, 13231–13236.