Crystal structure of the interleukin-4/receptor alpha chain complex reveals a mosaic binding interface

Interleukin-4 (IL-4) is a principal regulatory cytokine during an immune re sponse and a crucial determinant for allergy and asthma. IL-4 binds with hi gh affinity and specificity to the ectodomain of the IL-4 receptor cu chain (IL4-BP). Subsequently, this intermediate complex recruits the common gamm a chain (gamma c), thereby initiating transmembrane signaling. The crystal structure of the intermediate complex between human IL-4 and IL4-BP was det ermined at 2.3 Angstrom resolution. It reveals a novel spatial orientation of the two proteins, a small but unexpected conformational change in the re ceptor-bound IL-4, and an interface with three separate clusters of trans-i nteracting residues. Novel insights on ligand binding in the cytokine recep tor family and a paradigm for receptors of IL-2, IL-7, IL-9, and IL-15, whi ch all utilize gamma c, are provided.