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Publication Abstract from PubMed

IgE antibodies bind the high-affinity IgE Fc receptor (FcepsilonRI), found primarily on mast cells and basophils, and trigger inflammatory cascades of the allergic response. Inhibitors of IgE-FcepsilonRI binding have been identified and an anti-IgE therapeutic antibody (omalizumab) is used to treat severe allergic asthma. However, preformed IgE-FcepsilonRI 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-FcepsilonRI 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-FcepsilonRI 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-FcepsilonRI 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.

Accelerated disassembly of IgE-receptor complexes by a disruptive macromolecular inhibitor.,Kim B, Eggel A, Tarchevskaya SS, Vogel M, Prinz H, Jardetzky TS Nature. 2012 Nov 22;491(7425):613-7. doi: 10.1038/nature11546. Epub 2012 Oct 28. PMID:23103871^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.