Structure of the activation domain of the GM-CSF/IL3/IL-5 receptor common beta-chain bound to an antagonist

Heterodimeric cytokine receptors generally consist of a major cytokine-bind ing subunit and a signaling subunit. The latter can transduce signals by mo re than 1 cytokine, as exemplified by the granulocyte-macrophage colony-sti mulating factor (GM-CSF), interleukin-2 (IL-2), and IL-6 receptor systems. However, often the signaling subunits in isolation are unable to bind cytok ines, a fact that has made it more difficult to obtain structural definitio n of their ligand-binding sites. This report details the crystal structure of the ligand-binding domain of the GM-CSF/IL-3/IL-5 receptor beta-chain (b eta(c)) signaling subunit in complex with the Feb fragment of the antagonis tic monoclonal antibody, BION-1. This is the first single antagonist of all 3 known eosinophil-producing cytokines, and it is therefore capable of reg ulating eosinophil-related diseases such as asthma. The structure reveals a fibronectin type III domain, and the antagonist-binding site involves majo r contributions from the loop between the B and C strands and overlaps the cytokine-binding site. Furthermore, tyrosine(421) (Ty(421)), a key residue involved in receptor activation, lies in the neighboring loop between the F and G strands, although it is not immediately adjacent to the cytokine-bin ding residues in the B-C loop. Interestingly, functional experiments using receptors mutated across these loops demonstrate that they are cooperativel y involved in full receptor activation. The experiments, however, reveal su btle differences between the B-C loop and Tyr(421), which is suggestive of distinct functional roles. The elucidation of the structure of the ligand-b inding domain of beta(c) also suggests how different cytokines recognize a single receptor subunit, which may have implications for homologous recepto r systems. (Blood. 2000;95:2491-2498) (C) 2000 by The American Society of H ematology.