4GRG

Crystal structure of IgE complexed with E2_79, an anti-IgE inhibitor

4GRG の概要

• エントリーDOI: 10.2210/pdb4grg/pdb
• 分子名称: ANTI-IGE INHIBITOR E2_79, Ig epsilon chain C region (2 entities in total)
• 機能のキーワード: ig-fold, immunity, high/low affinity receptor, immune system-inhibitor complex, immune system/inhibitor
• 由来する生物種: Escherichia coli; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 80570.30

構造登録者

Kim, B.,Jardetzky, T.S. (登録日: 2012-08-24, 公開日: 2012-12-12, 最終更新日: 2019-07-17)

主引用文献

Kim, B.,Eggel, A.,Tarchevskaya, S.S.,Vogel, M.,Prinz, H.,Jardetzky, T.S.
Accelerated disassembly of IgE-receptor complexes by a disruptive macromolecular inhibitor.
Nature, 491:613-617, 2012

PubMed Abstract: IgE antibodies bind the high-affinity IgE Fc receptor (FcεRI), found primarily on mast cells and basophils, and trigger inflammatory cascades of the allergic response. Inhibitors of IgE-FcεRI binding have been identified and an anti-IgE therapeutic antibody (omalizumab) is used to treat severe allergic asthma. However, preformed IgE-FcεRI complexes that prime cells before allergen exposure dissociate extremely slowly and cannot be disrupted by strictly competitive inhibitors. IgE-Fc conformational flexibility indicated that inhibition could be mediated by allosteric or other non-classical mechanisms. Here we demonstrate that an engineered protein inhibitor, DARPin E2_79 (refs 9, 10, 11), acts through a non-classical inhibition mechanism, not only blocking IgE-FcεRI interactions, but actively stimulating the dissociation of preformed ligand-receptor complexes. The structure of the E2_79-IgE-Fc(3-4) complex predicts the presence of two non-equivalent E2_79 sites in the asymmetric IgE-FcεRI complex, with site 1 distant from the receptor and site 2 exhibiting partial steric overlap. Although the structure is indicative of an allosteric inhibition mechanism, mutational studies and quantitative kinetic modelling indicate that E2_79 acts through a facilitated dissociation mechanism at site 2 alone. These results demonstrate that high-affinity IgE-FcεRI complexes can be actively dissociated to block the allergic response and suggest that protein-protein complexes may be more generally amenable to active disruption by macromolecular inhibitors.

PubMed: 23103871
DOI: 10.1038/nature11546

実験手法

X-RAY DIFFRACTION (4.24 Å)