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PDBsum entry 3hmw
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Immune system
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PDB id
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3hmw
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References listed in PDB file
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Key reference
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Title
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Structural basis for the dual recognition of il-12 and il-23 by ustekinumab.
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Authors
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J.Luo,
S.J.Wu,
E.R.Lacy,
Y.Orlovsky,
A.Baker,
A.Teplyakov,
G.Obmolova,
G.A.Heavner,
H.T.Richter,
J.Benson.
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Ref.
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J Mol Biol, 2010,
402,
797-812.
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PubMed id
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Abstract
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Interleukin (IL)-12 and IL-23 are heterodimeric proinflammatory cytokines that
share a common p40 subunit, paired with p35 and p19 subunits, respectively. They
represent an attractive class of therapeutic targets for the treatment of
psoriasis and other immune-mediated diseases. Ustekinumab is a fully human
monoclonal antibody (mAb) that binds specifically to IL-12/IL-23p40 and
neutralizes human IL-12 and IL-23 bioactivity. The crystal structure of
ustekinumab Fab (antigen binding fragment of mAb), in complex with human IL-12,
has been determined by X-ray crystallography at 3.0 Å resolution. Ustekinumab
Fab binds the D1 domain of the p40 subunit in a 1:1 ratio in the crystal,
consistent with a 2 cytokines:1 mAb stoichiometry, as measured by isothermal
titration calorimetry. The structure indicates that ustekinumab binds to the
same epitope on p40 in both IL-12 and IL-23 with identical interactions.
Mutational analyses confirm that several residues identified in the
IL-12/IL-23p40 epitope provide important molecular binding interactions with
ustekinumab. The electrostatic complementarity between the mAb antigen binding
site and the p40 D1 domain epitope appears to play a key role in
antibody/antigen recognition specificity. Interestingly, this structure also
reveals significant structural differences in the p35 subunit and p35/p40
interface, compared with the published crystal structure of human IL-12,
suggesting unusual and potentially functionally relevant structural flexibility
of p35, as well as p40/p35 recognition. Collectively, these data describe unique
observations about IL-12p35 and ustekinumab interactions with p40 that account
for its dual binding and neutralization of IL-12 and IL-23.
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