Abstract
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
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Arginine / genetics
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Arginine / metabolism
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Binding Sites
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Crystallography, X-Ray
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Dimerization
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Disulfides / chemistry
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Disulfides / metabolism
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Drug Design
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Epitopes / chemistry
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Epitopes / metabolism
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Growth Hormone / chemistry
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Growth Hormone / metabolism
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Humans
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Interleukin-12 / antagonists & inhibitors
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Interleukin-12 / chemistry*
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Interleukin-12 / genetics
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Interleukin-12 / metabolism
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Models, Molecular
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Molecular Weight
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Mutagenesis, Site-Directed
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Protein Binding
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Receptors, Cytokine / antagonists & inhibitors
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Receptors, Cytokine / chemistry
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Receptors, Cytokine / genetics
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Receptors, Cytokine / metabolism
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Receptors, Somatotropin / chemistry
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Receptors, Somatotropin / metabolism
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Signal Transduction
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Static Electricity
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Structure-Activity Relationship
Substances
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Disulfides
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Epitopes
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Receptors, Cytokine
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Receptors, Somatotropin
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Interleukin-12
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Growth Hormone
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Arginine