Crystal Structure of the Interleukin-4/Receptor α Chain Complex Reveals a Mosaic Binding Interface

a chain (Hoffman et al., 1995; Shen et al., 1996). Its Interleukin-4 (IL-4) is a principal regulatory cytokine primary structure reveals features of a cytokine recepduring an immune response and a crucial determinant tor homology domain (CHR) and exhibits maximal sefor allergy and asthma. IL-4 binds with high affinity quence similarity with ectodomains of type I cytokine and specificity to the ectodomain of the IL-4 receptor receptors that interact with short chain or long chain a chain (IL4-BP). Subsequently, this intermediate comhelical cytokines and form homodimeric or heterodiplex recruits the common g chain (gc), thereby initiatmeric receptors in the membrane (Bazan, 1990). ing transmembrane signaling. The crystal structure of The structure of receptor-unbound human IL-4 has the intermediate complex between human IL-4 and been described in crystals and in solution (Powers et IL4-BP was determined at 2.3 Å resolution. It reveals al., 1992; Smith et al., 1992; Walter et al., 1992; Wlodawer a novel spatial orientation of the two proteins, a small et al., 1992). It resembles structures of other short chain but unexpected conformational change in the recepfour-helix bundle cytokines (Sprang and Bazan, 1993) tor-bound IL-4, and an interface with three separate such as GM-CSF, IL-2, and IL-5 and exhibits the same clusters of trans-interacting residues. Novel insights helix topology and connectivity as the long chain fouron ligand binding in the cytokine receptor family and helix bundle cytokines including hGH, EPO, IL-6, and a paradigm for receptors of IL-2, IL-7, IL-9, and IL-15, G-CSF (Sprang and Bazan, 1993; Rozwarski et al., 1994). which all utilize gc, are provided. The functional epitope of IL-4 that determines the