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Structural basis for selective inhibition of immunoglobulin E-receptor interactions by an anti-IgE antibody

Chen, J-B; Ramadani, F; Pang, MOY; Beavil, RL; Holdom, MD; Mitropoulou, AN; Beavil, AJ; ... Davies, AM; + view all (2018) Structural basis for selective inhibition of immunoglobulin E-receptor interactions by an anti-IgE antibody. Scientific Reports , 8 , Article 11548. 10.1038/s41598-018-29664-4. Green open access

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Abstract

Immunoglobulin E (IgE) antibodies play a central role in the allergic response: interaction with FcεRI on mast cells and basophils leads to immediate hypersensitivity reactions upon allergen challenge, while interaction with CD23/FcεRII, expressed on a variety of cells, regulates IgE synthesis among other activities. The receptor-binding IgE-Fc region has recently been found to display remarkable flexibility, from acutely bent to extended conformations, with allosteric communication between the distant FcεRI and CD23 binding sites. We report the structure of an anti-IgE antibody Fab (8D6) bound to IgE-Fc through a mixed protein-carbohydrate epitope, revealing further flexibility and a novel extended conformation with potential relevance to that of membrane-bound IgE in the B cell receptor for antigen. Unlike the earlier, clinically approved anti-IgE antibody omalizumab, 8D6 inhibits binding to FcεRI but not CD23; the structure reveals how this discrimination is achieved through both orthosteric and allosteric mechanisms, supporting therapeutic strategies that retain the benefits of CD23 binding.

Type: Article
Title: Structural basis for selective inhibition of immunoglobulin E-receptor interactions by an anti-IgE antibody
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41598-018-29664-4
Publisher version: https://doi.org/10.1038/s41598-018-29664-4
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, FC-EPSILON-RI, B-CELLS, AFFINITY RECEPTOR, CRYSTAL-STRUCTURE, MACROMOLECULAR CRYSTALLOGRAPHY, CONFORMATIONAL FLEXIBILITY, ALLERGIC DISEASE, HYPER IGE, CD23, BINDING
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10055321
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