(485a) A Novel Cytokine Recognition Mode in the Structure of Interleukin-2 Complexed with Its Alpha Receptor

Interleukin-2 is the key immunoregulatory cytokine that modulates T cell growth, effector function, and cell survival. IL-2 carries out its functions through the sequential assembly of specific IL-2 alpha (RA) and beta (RB) receptors with the common gamma chain (Gc) receptor. Despite the compelling importance of IL-2 in basic and clinical immunology, the structural basis of its receptor interactions is unknown. Here we present the 2.8Å crystal structure of a complex between human IL-2 and its RA, which interact in a docking mode previously unseen in other cytokine receptor complexes. RA appears to ?cap? the top of the cytokine for presentation to RB and Gc, and subsequent formation of the quaternary signaling complex. The RA structure is composed of two beta strand-swapped ?sushi-like? domains that deviate from the classical cytokine receptor fold. The strand swapping in RA results in the formation of a hybrid beta sheet which docks into a groove on the surface of II-2 through a core hydrophobic hotspot surrounded by charged contacts. Strikingly, this groove on IL-2 also serves as the binding site for antagonist small molecules. RA induces an identical conformation of the IL-2 AB-loop to that seen in IL-2 complexed with drug, suggesting a selection for a ?receptor-competent? IL-2 isomer by both drug and RA. Visualization of this novel interaction can now facilitate the improvement of inhibitors of IL-2 for a variety of lymphoproliferative diseases and immunosuppressive therapies.