Charged residues dominate a unique interlocking topography in the heterodimeric cytokine interleukin-12.
Human interleukin-12 (IL-12, p70) is an early pro-inflammatory cytokine, comprising two disulfide-linked subunits, p35 and p40. We solved the crystal structures of monomeric human p40 at 2.5 A and the human p70 complex at 2.8 A 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 charged residues from p35 and p40 intercalate to form a unique interlocking topography, 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.
Mesh Terms:
Arginine, Binding Sites, Crystallography, X-Ray, Dimerization, Disulfides, Drug Design, Epitopes, Growth Hormone, Humans, Interleukin-12, Models, Molecular, Molecular Weight, Mutagenesis, Site-Directed, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, Receptors, Cytokine, Receptors, Somatotropin, Signal Transduction, Static Electricity, Structure-Activity Relationship
Arginine, Binding Sites, Crystallography, X-Ray, Dimerization, Disulfides, Drug Design, Epitopes, Growth Hormone, Humans, Interleukin-12, Models, Molecular, Molecular Weight, Mutagenesis, Site-Directed, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, Receptors, Cytokine, Receptors, Somatotropin, Signal Transduction, Static Electricity, Structure-Activity Relationship
EMBO J.
Date: Jul. 17, 2000
PubMed ID: 10899108
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