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PDBsum entry 1f42
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Charged residues dominate a unique interlocking topography in the heterodimeric cytokine interleukin-12.
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Authors
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C.Yoon,
S.C.Johnston,
J.Tang,
M.Stahl,
J.F.Tobin,
W.S.Somers.
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Ref.
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EMBO J, 2000,
19,
3530-3541.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 1.
Figure 1 p40 resembles a soluble class 1 cytokine  -receptor.
N- and C-termini are labeled N and C, respectively, and the
three domains are labeled D1, D2 and D3. The intrachain
disulfide bonds (yellow), an N-linked sugar modification (red)
and the WSXWS motif (magenta) are shown. The p40 loops that
contact p35 (turquoise) are located at the apex between D2 and
D3. Flexible loop regions are indicated by dotted lines. This
and all subsequent figures (except Figures 3 and 7) were made
using MOLSCRIPT (Kraulis, 1991) and Raster3D (Merritt and Bacon,
1997).
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Figure 4.
Figure 4 Important charged interactions in the p35–p40 binding
interface. (A) R189 (yellow) from p35 helix D projects into a
deep, hydrophobic pocket composed of p40 loops 1, 5, 6 (thick)
and 3 (thin). A buried hydrogen bonding network (dashes)
connects R189 with D290 from p40 through a bound water (red
sphere). (B) E181 in p40 is part of a second important charged
interaction. Dashed lines indicate hydrogen bonding of p40 E181
with p35 residues R183 and T186. R183 is further stabilized by
electrostatic interactions with p35 D108 in helix B.
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The above figures are
reprinted
from an Open Access publication published by Macmillan Publishers Ltd:
EMBO J
(2000,
19,
3530-3541)
copyright 2000.
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