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PDBsum entry 2vxv
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Immune system
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PDB id
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2vxv
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References listed in PDB file
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Key reference
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Title
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Unusual water-Mediated antigenic recognition of the proinflammatory cytokine interleukin-18.
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Authors
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M.A.Argiriadi,
T.Xiang,
C.Wu,
T.Ghayur,
D.W.Borhani.
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Ref.
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J Biol Chem, 2009,
284,
24478-24489.
[DOI no: ]
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PubMed id
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Abstract
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The unique cytokine interleukin-18 (IL-18) acts synergistically with IL-12 to
regulate T-helper 1 and 2 lymphocytes and, as such, seems to underlie the
pathogenesis of various autoimmune and allergic diseases. Several anti-IL-18
agents are in clinical development, including the recombinant human antibody
ABT-325, which is entering trials for autoimmune diseases. Given competing
cytokine/receptor and cytokine/receptor decoy interactions, understanding the
structural basis for recognition is critical for effective development of
anti-cytokine therapies. Here we report three crystal structures: the murine
antibody 125-2H Fab fragment bound to human IL-18, at 1.5 A resolution; the
125-2H Fab (2.3 A); and the ABT-325 Fab (1.5 A). These structures, along with
human/mouse IL-18 chimera binding data, allow us to make three key observations
relevant to the biology and antigenic recognition of IL-18 and related
cytokines. First, several IL-18 residues shift dramatically (> 10 A) upon
binding 125-2H, compared with unbound IL-18 (Kato, Z., Jee, J., Shikano, H.,
Mishima, M., Ohki, I., Ohnishi, H., Li, A., Hashimoto, K., Matsukuma, E., Omoya,
K., Yamamoto, Y., Yoneda, T., Hara, T., Kondo, N., and Shirakawa, M. (2003) Nat.
Struct. Biol. 10, 966-971). IL-18 thus exhibits plasticity that may be common to
its interactions with other receptors. Related cytokines may exhibit similar
plasticity. Second, ABT-325 and 125-2H differ significantly in combining site
character and architecture, thus explaining their ability to bind IL-18
simultaneously at distinct epitopes. These data allow us to define the likely
ABT-325 epitope and thereby explain the distinct neutralizing mechanisms of both
antibodies. Third, given the high 125-2H potency, 10 well ordered water
molecules are trapped upon complex formation in a cavity between two IL-18 loops
and all six 125-2H complementarity-determining regions. Thus,
counterintuitively, tight and specific antibody binding may in some cases be
water-mediated.
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Figure 2.
125-2H binds human IL-18 residue Leu^180 in a deep pocket,
trapping 10 water molecules. a, overview of the complex. The
antibody engages the primary (Leu^180) and secondary (Pro^143)
IL-18 loops. IL-18 is colored as a rainbow, from the NH[2] to
the COOH terminus; CDRs 1, 2, and 3 of the 125-2H Fab fragment
(purple, heavy chain; pink, light chain) are colored orange,
yellow, and green, with the heavy chain in darker tones. The
solvent-inaccessible, water-filled cavity trapped between 125-2H
Fab and IL-18 is shown (brown dots). b, the center of the
combining site, viewed from the perspective of IL-18 (gray).
Note the deep hydrophobic pocket, formed by heavy and light
chain Tyr and Leu residues, that binds Leu^180. c, the periphery
of the combining site is ringed by charge-charge and hydrogen
bonding interactions involving all six 125-2H CDRs. d,
stereoview illustrating the large cavity (brown dots) formed
between the IL-18 primary and secondary loops and the 125-2H
CDRs, trapping 10 well ordered water molecules. The detailed
hydrogen bond interactions are shown in supplemental Fig. 2.
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Figure 6.
Multiple IL-18 epitopes mediate binding to multiple
receptors. IL-18Rα and IL-18BP were modeled based on the IL-1R1
crystal structure (13) (Protein Data Bank entry 1ITB) and are
shown bound to IL-18. a, engagement of IL-18 (gray) by IL-18Rα
completely blocks the proposed ABT-325 epitope (magenta), and
β-strands B and D (red) in domain 2 collide with 125-2H CDR H2.
The IL-18BP (red) and IL-18Rβ (green; “Site 3” (see Ref.
1)) epitopes are also shown. b, close up view of the collision
between 125-2H and IL-18Rα, viewed from behind relative to a.
c, 125-2H, ABT-325, and IL-18BP can all bind IL-18
simultaneously, since their epitopes do not overlap.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2009,
284,
24478-24489)
copyright 2009.
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