Davies, AM;
Allan, EG;
Keeble, AH;
Delgado, J;
Cossins, BP;
Mitropoulou, AN;
Pang, MOY;
... Sutton, BJ; + view all
(2017)
Allosteric mechanism of action of the therapeutic anti-IgE antibody omalizumab.
The Journal of Biological Chemistry
, 292
(24)
pp. 9975-9987.
10.1074/jbc.M117.776476.
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Abstract
Immunoglobulin E and its interactions with receptors FcϵRI and CD23 play a central role in allergic disease. Omalizumab, a clinically approved therapeutic antibody, inhibits the interaction between IgE and FcϵRI, preventing mast cell and basophil activation, and blocks IgE binding to CD23 on B cells and antigen-presenting cells. We solved the crystal structure of the complex between an omalizumab-derived Fab and IgE-Fc, with one Fab bound to each Cϵ3 domain. Free IgE-Fc adopts an acutely bent structure, but in the complex it is only partially bent, with large-scale conformational changes in the Cϵ3 domains that inhibit the interaction with FcϵRI. CD23 binding is inhibited sterically due to overlapping binding sites on each Cϵ3 domain. Studies of omalizumab Fab binding in solution demonstrate the allosteric basis for FcϵRI inhibition and, together with the structure, reveal how omalizumab may accelerate dissociation of receptor-bound IgE from FcϵRI, exploiting the intrinsic flexibility and allosteric potential of IgE.
Type: | Article |
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Title: | Allosteric mechanism of action of the therapeutic anti-IgE antibody omalizumab |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1074/jbc.M117.776476 |
Publisher version: | http://dx.doi.org/%2010.1074/jbc.M117.776476 |
Language: | English |
Additional information: | © 2017 by The American Society for Biochemistry and Molecular Biology, Inc. This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) |
Keywords: | Allergy, Allosteric regulation, Antibody, Immunoglobulin E (IgE), X-ray crystallography, Omalizumab |
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/10041051 |
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