Interleukin-2 – Interleukin-2 receptor subunit alpha binding interface (IL-2/IL-2Rα interface)

The Human interleukin-2 – IL-2Rα binding interface is a pivotal protein-protein interaction site essential for the assembly of the high-affinity IL-2 receptor complex. Interleukin-2 (IL-2) is a key cytokine that promotes the proliferation and differentiation of T-cells, and its interaction with the alpha subunit (IL-2Rα or CD25) increases the binding affinity by approximately 100-fold compared to the dimeric IL-2Rβγ complex alone (UniProt P01589). This interface is a primary target for immunosuppressive therapies, particularly in the prevention of acute organ transplant rejection, where monoclonal antibodies like Basiliximab bind to CD25 to block IL-2 from initiating T-cell expansion (StatPearls, NBK537133). In addition to transplantation, this interface is being explored in the context of autoimmune diseases and oncology, where "IL-2 mimetics" or "biased" IL-2 variants are designed to either bypass or selectively utilize this interface to modulate the balance between effector T-cells and regulatory T-cells (Rickert et al., 2005, PMID: 16103334). Understanding the structural biology of this interface has been crucial for developing drugs that can finely tune the immune response by targeting specific T-cell subsets. The interface involves specific residues on IL-2 (such as Lys35, Arg38, Phe42, and Lys43) and IL-2Rα that form a complementary surface (Wang et al., 2005, PMID: 16103334). Therapeutic modulation of this site allows for precise control over T-cell mediated immunity, making it a cornerstone of modern immunopharmacology.

Other names

IL-2/CD25 interfaceIL-2/IL-2RA interfaceIL-2/p55 interfaceInterleukin-2/CD25 binding site

Competitive inhibition of the interaction between interleukin-2 and the alpha subunit (CD25) of its receptor, which prevents the formation of the high-affinity heterotrimeric receptor complex (IL-2Rαβγ) and subsequent downstream signaling via the JAK/STAT pathway (Wang et al., 2005, PMID: 16103334).