AbstractInterleukin‐5 (IL‐5), a major hematopoietin, stimulates eosinophil proliferation, migration, and activation, which have been implicated in the pathogenesis of allergic inflammatory diseases, such as asthma. The specific IL‐5 receptor (IL‐5R) consists of the IL‐5 receptor α subunit (IL‐5RA) and the common receptor β subunit (βc). IL‐5 binding to IL‐5R on target cells induces rapid tyrosine phosphorylation and activation of various cellular proteins, including JAK1/JAK2 and STAT1/STAT5. Here, we report the crystal structure of dimeric IL‐5 in complex with the IL‐5RA extracellular domains. The structure revealed that IL‐5RA sandwiches the IL‐5 homodimer by three tandem domains, arranged in a “wrench‐like” architecture. This association mode was confirmed for human cells expressing IL‐5 and the full‐length IL‐5RA by applying expanded genetic code technology: protein photo‐cross‐linking experiments revealed that the two proteins interact with each other in vivo in the same manner as that in the crystal structure. Furthermore, a comparison with the previously reported, partial GM‐CSF•GM‐CSFRA•βc structure enabled us to propose complete structural models for the IL‐5 and GM‐CSF receptor complexes, and to identify the residues conferring the cytokine‐specificities of IL‐5RA and GM‐CSFRA.