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PDBsum entry 3duh
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Immune system/cytokine
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PDB id
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3duh
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Contents |
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300 a.a.
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137 a.a.
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137 a.a.
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References listed in PDB file
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Key reference
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Title
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The structure of interleukin-23 reveals the molecular basis of p40 subunit sharing with interleukin-12.
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Authors
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P.J.Lupardus,
K.C.Garcia.
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Ref.
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J Mol Biol, 2008,
382,
931-941.
[DOI no: ]
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PubMed id
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Abstract
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Interleukin (IL)-23 is a recently identified member of the IL-12 family of
heterodimeric cytokines that modulate subpopulations of T helper cells, and both
IL-12 and IL-23 are attractive targets for therapy of autoimmune diseases. IL-23
is a binary complex of a four-helix bundle cytokine (p19) and a soluble class I
cytokine receptor p40. IL-12 and IL-23 share p40 as an alpha-receptor subunit,
yet show only 15% sequence homology between their four-helix cytokines p19 and
p35, respectively, and signal through different combinations of shared
receptors. In order to elucidate the structural basis of p40 sharing, we have
determined a 2.3-A crystal structure of IL-23 for comparison to the previously
determined structure of IL-12. The docking mode of p19 to p40 is altered
compared to p35, deviating by a 'tilt' and 'roll' that results in an altered
footprint of p40 on the A and D helices of the respective cytokines. Binding of
p19 to p40 is mediated primarily by an arginine residue on helix D of p19 that
forms an extensive charge and hydrogen-bonding network with residues at the base
of a pocket on p40. This 'arginine pocket' is lined with an inner shell of
hydrophobic interactions that are ringed by an outer shell of polar
interactions. Comparative analysis indicates that the IL-23 and IL-12 complexes
'mimic' the network of interactions constituting the central arginine pocket
despite p19 and p35 having limited sequence homology. The majority of the
structural epitopes in the two complexes are composed of unique p19 and p35
pairwise contacts with common residues on p40. Thus, while the critical hotspot
is maintained in the two complexes, the majority of the interfaces are
structurally distinct and, therefore, provide a basis for the therapeutic
targeting of IL-12 versus IL-23 heterodimer formation despite their use of a
common receptor subunit.
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Figure 2.
Fig. 2. Structure of IL-23. (a) Side view of the IL-23
crystal structure. p19 helices A to D are colored magenta, and
p40 domains 1 to 3 are colored blue. The single
N-acetylglucosamine residue attached to Asn200 on p40 is shown
in red. Disulfide linkages are colored yellow. (b) Face-on view
of IL-23. Receptor interaction sites 2 and 3 are highlighted in
ovals, and the key site 3-interacting side chain of Trp137 is
displayed.
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Figure 5.
Fig. 5. Comparison of shared and distinct contact surfaces in
the IL-23 and IL-12 complexes. (a) Histogram of buried surface
area contributed by each p40 residue involved in p19 and/or p35
interaction. (b) Surface representation of p40 (middle panel),
with residues interacting with p19 (pink), p35 (green), or p19
and p35 (yellow) highlighted. The p40-interacting surfaces of
p19 (left panel in pink) and p35 (right panel in green) are
shown with a transparent p40 overlay to demonstrate orientation.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2008,
382,
931-941)
copyright 2008.
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