2VXT

Crystal structure of human IL-18 complexed to murine reference antibody 125-2H Fab

2VXT の概要

• エントリーDOI: 10.2210/pdb2vxt/pdb
• 関連するPDBエントリー: 1J0S 2VXU 2VXV
• 分子名称: MURINE IGG 125-2H, INTERLEUKIN-18, CHLORIDE ION, ... (6 entities in total)
• 機能のキーワード: fab, il-18, secreted, cytokine, autoimmunity, glycoprotein, th1/th2 cells, immunoglobulin domain, immunoglobulin v region
• 由来する生物種: MUS MUSCULUS (MOUSE); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 65092.66

構造登録者

Argiriadi, M.A.,Xiang, T.,Wu, C.,Ghayur, T.,Borhani, D.W. (登録日: 2008-07-10, 公開日: 2009-06-23, 最終更新日: 2024-11-13)

主引用文献

Argiriadi, M.A.,Xiang, T.,Wu, C.,Ghayur, T.,Borhani, D.W.
Unusual Water-Mediated Antigenic Recognition of the Proinflammatory Cytokine Interleukin-18.
J.Biol.Chem., 284:24478-, 2009

PubMed Abstract: 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.

PubMed: 19553661
DOI: 10.1074/JBC.M109.023887

実験手法

X-RAY DIFFRACTION (1.49 Å)