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Allosteric mechanism of action of the therapeutic anti-IgE antibody omalizumab

Research output: Contribution to journalArticlepeer-review

Anna M. Davies, Elizabeth G. Allan, Anthony H. Keeble, Jean Delgado, Benjamin P Cossins, Alkistis N. Mitropoulou, Marie O.Y. Pang, Tom Ceska, Andrew J. Beavil, Graham Craggs, Marta Westwood, Alistair J. Henry, James M. McDonnell, Brian J. Sutton

Original languageEnglish
Pages (from-to)9975–9987
JournalJournal of Biological Chemistry
Issue number24
Early online date24 Apr 2017
Accepted/In press24 Apr 2017
E-pub ahead of print24 Apr 2017
Published16 Jun 2017


  • Allosteric mechanism of action_DAVIES_Publishedonline24April2017_GOLD VoR (CC-BY)

    Allosteric_mechanism_of_action_DAVIES_Publishedonline24April2017_GOLD_VoR_CC_BY_.pdf, 4.03 MB, application/pdf

    Uploaded date:29 Jun 2017

    Version:Final published version

    Licence:CC BY

    This research was originally published in Journal of Biological Chemistry. Davies et. al. "Allosteric mechanism of action of the therapeutic anti-IgE
    antibody omalizumab". JBC, 2017; Vol 292 (24) : 9975-9987 © the American Society for Biochemistry and Molecular Biology.

King's Authors


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.

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