3HMW

Crystal structure of ustekinumab FAB

3HMW の概要

• エントリーDOI: 10.2210/pdb3hmw/pdb
• 分子名称: USTEKINUMAB FAB LIGHT CHAIN, USTEKINUMAB FAB HEAVY CHAIN, CADMIUM ION, ... (4 entities in total)
• 機能のキーワード: ustekinumab, cnto1275, il-12, il-23, antibody, fab, monoclonal antibody, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 48061.27

構造登録者

Luo, J. (登録日: 2009-05-29, 公開日: 2010-06-09, 最終更新日: 2024-11-20)

主引用文献

Luo, J.,Wu, S.J.,Lacy, E.R.,Orlovsky, Y.,Baker, A.,Teplyakov, A.,Obmolova, G.,Heavner, G.A.,Richter, H.T.,Benson, J.
Structural basis for the dual recognition of IL-12 and IL-23 by ustekinumab.
J.Mol.Biol., 402:797-812, 2010

PubMed Abstract: 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.

PubMed: 20691190
DOI: 10.1016/j.jmb.2010.07.046

実験手法

X-RAY DIFFRACTION (3 Å)