Charged residues dominate a unique interlocking topography in the heterodimeric cytokine interleukin-12

Human interleukin-12 (IL-12, p70) is an early proinflammatory cytokine, com prising two disulfide-linked subunits, p35 and p40. We solved the crystal s tructures of monomeric human p40 at 2.5 Angstrom and the human p70 complex at 2.8 Angstrom resolution, which reveals that IL-12 is similar to class 1 cytokine-receptor complexes. They also include the first description of an N-terminal immunoglobulin-like domain, found on the p40 subunit, Several ch arged residues from p35 and p40 intercalate to form a unique interlocking t opography, shown by mutagenesis to be critical for p70 formation, A central arginine residue from p35 projects into a deep pocket on p40, which may be an ideal target for a small molecule antagonist of IL-12 formation.