Abstract
Interleukin (IL)-23 is a pro-inflammatory cytokine playing a key role in the pathogenesis of several autoimmune and inflammatory diseases. We have determined the crystal structures of the heterodimeric p19-p40 IL-23 and its complex with the Fab (antigen-binding fragment) of a neutralizing antibody at 2.9 and 1.9 A, respectively. The IL-23 structure closely resembles that of IL-12. They share the common p40 subunit, and IL-23 p19 overlaps well with IL-12 p35. Along the hydrophilic heterodimeric interface, fewer charged residues are involved for IL-23 compared with IL-12. The binding site of the Fab is located exclusively on the p19 subunit, and comparison with published cytokine-receptor structures suggests that it overlaps with the IL-23 receptor binding site.
MeSH terms
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Amino Acid Sequence
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Antibodies, Monoclonal / chemistry*
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Antibodies, Monoclonal / genetics
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Antibodies, Monoclonal / immunology
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Binding Sites
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Crystallography, X-Ray
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Dimerization
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Humans
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Immunoglobulin Fab Fragments / chemistry*
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Immunoglobulin Fab Fragments / genetics
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Immunoglobulin Fab Fragments / immunology
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Inflammation / immunology*
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Interleukin-12 Subunit p40 / chemistry*
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Interleukin-12 Subunit p40 / genetics
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Interleukin-12 Subunit p40 / immunology
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Interleukin-23 Subunit p19 / chemistry*
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Interleukin-23 Subunit p19 / genetics
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Interleukin-23 Subunit p19 / immunology
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Models, Molecular
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Molecular Sequence Data
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Protein Conformation*
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Receptors, Cytokine / chemistry
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Receptors, Cytokine / metabolism
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Receptors, Interleukin / chemistry
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Receptors, Interleukin / genetics
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Receptors, Interleukin / immunology
Substances
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Antibodies, Monoclonal
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IL23R protein, human
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Immunoglobulin Fab Fragments
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Interleukin-12 Subunit p40
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Interleukin-23 Subunit p19
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Receptors, Cytokine
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Receptors, Interleukin