4G5Z

Crystal structure of the therapeutical antibody fragment of canakinumab in its unbound state

4G5Z の概要

• エントリーDOI: 10.2210/pdb4g5z/pdb
• 関連するPDBエントリー: 4G6J 4G6K 4G6M
• 分子名称: canakinumab antibody fragment heavy chain, canakinumab antibody fragment light chain (3 entities in total)
• 機能のキーワード: immunoglobulin fold, antibody, immunoglobulin, interleukine-1beta binding, cytokine, blood system, immune system
• 由来する生物種: homo sapiens (humans); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 46498.80

構造登録者

Blech, M.,Hoerer, S. (登録日: 2012-07-18, 公開日: 2012-12-19, 最終更新日: 2024-10-16)

主引用文献

Blech, M.,Peter, D.,Fischer, P.,Bauer, M.M.,Hafner, M.,Zeeb, M.,Nar, H.
One target-two different binding modes: Structural insights into gevokizumab and canakinumab interactions to interleukin-1beta
J.Mol.Biol., 425:94-111, 2013

PubMed Abstract: Interleukin-1β (IL-1β) is a key orchestrator in inflammatory and several immune responses. IL-1β exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1β monoclonal antibodies. Canakinumab is known to neutralize IL-1β by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1β bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1β signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1β. Furthermore, we characterized the epitopes on IL-1β employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X-ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1β and provide insight into the mechanisms leading to their distinct modulation of IL-1β signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1β causes competitive inhibition of the association of IL-1β and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1β and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1β pathway attenuation.

PubMed: 23041424
DOI: 10.1016/j.jmb.2012.09.021

実験手法

X-RAY DIFFRACTION (1.83 Å)