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.
Yoon
C
C
Departments of Musculoskeletal Sciences and Biological Chemistry, Wyeth Research, 87 Cambridge Park Drive, Cambridge, MA 02140, USA.
Johnston
S C
SC
Tang
J
J
Stahl
M
M
Tobin
J F
JF
Somers
W S
WS
D001120:Arginine / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D000939:Epitopes / Q000737:chemistry / Q000378:metabolism; D013006:Growth Hormone / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008970:Molecular Weight; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D055672:Static Electricity; D013329:Structure-Activity Relationship
D004220:Disulfides; D000939:Epitopes; D018121:Receptors, Cytokine; D011986:Receptors, Somatotropin; D018664:Interleukin-12; D013006:Growth Hormone; D001120:Arginine