Crystal structures of the pro-inflammatory cytokine interleukin-23 and its complex with a high-affinity neutralizing antibody.
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.
Beyer
Brian M
BM
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Ingram
Richard
R
Ramanathan
Lata
L
Reichert
Paul
P
Le
Hung V
HV
Madison
Vincent
V
Orth
Peter
P
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D053762:Interleukin-12 Subunit p40 / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D053760:Interleukin-23 Subunit p19 / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D018121:Receptors, Cytokine / Q000737:chemistry / Q000378:metabolism; D018123:Receptors, Interleukin / Q000737:chemistry / Q000235:genetics / Q000276:immunology
D000911:Antibodies, Monoclonal; C515500:IL23R protein, human; D007140:Immunoglobulin Fab Fragments; D053762:Interleukin-12 Subunit p40; D053760:Interleukin-23 Subunit p19; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin