Accelerated disassembly of IgE-receptor complexes by a disruptive macromolecular inhibitor

Kim, Beomkyu; Eggel, Alexander; Tarchevskaya, Svetlana S; Vogel, Monique; Prinz, Heino; Jardetzky, Theodore S (2012). Accelerated disassembly of IgE-receptor complexes by a disruptive macromolecular inhibitor. Nature, 491(7425), pp. 613-7. London: Macmillan Journals Ltd. 10.1038/nature11546

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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.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute for Immunology [discontinued]
UniBE Contributor:	Eggel, Alexander, Vogel, Monique
ISSN:	0028-0836
Publisher:	Macmillan Journals Ltd.
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:37
Last Modified:	05 Dec 2022 14:11
Publisher DOI:	10.1038/nature11546
PubMed ID:	23103871
Web of Science ID:	000311339800056
URI:	https://boris.unibe.ch/id/eprint/15092 (FactScience: 222285)