Homology model of human interferon‐α8 and its receptor complex

Human interferon‐α8 (HuIFNα8), a type I interferon (IFN), is a cytokine belonging to the hematopoietic super‐family that includes human growth hormone (HGH). Recent data identified two human type I IFN receptor components. One component (p40) was purified from human urine by its ability to bind to immobilized type I IFN. A second receptor component (IFNAR), consisting of two cytokine receptor‐like domains (D200 and D200′), was identified by expression cloning. Murine cells transfected with a gene encoding this protein were able to produce an antiviral response to human IFNα8. Both of these receptor proteins have been identified as members of the immunoglobulin superfamily of which HGH receptor is a member. The cytokine receptor‐like structural motifs present in p40 and IFNAR were modeled based on the HGH receptor X‐ray structure. Models of the complexes of HuIFNα8 with the receptor subunits were built by superpositioning the conserved Cα backbone of the HuIFNα8 and receptor subunit models with HGH and its receptor complex. The HuIFNα8 model was constructed from the Cα coordinates of murine interferon‐β crystal structure. Electrostatic potentials and hydrophobic interactions appear to favor the model of HuIFNα8 interacting with p40 at site 1 and the D200′ domain of IFNAR at site 2 because there are regions of complementary electrostatic potential and hydrophobic interactions at both of the proposed binding interfaces. Some of the predicted receptor binding residues within HuIFNα8 correspond to functionally important residues determined previously for human IFNα1, IFNα2, and IFNα4 subtypes by site‐directed mutagenesis studies. The models predict regions of interaction between HuIFNα8 and each of the receptor proteins, and provide insights into interactions between other type I IFNs (IFN‐α subtypes and IFN‐β) and their respective receptor components.