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

DOI: 10.1074/jbc.M117.776476 DOI Help

Authors: Anna M. Davies (King’s College London; Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma) , Elizabeth G. Allan (King’s College London; Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma) , Anthony H. Keeble (King’s College London; Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma) , Jean Delgado (UCB Pharma) , Benjamin P. Cossins (UCB Pharma) , Alkistis N. Mitropoulou (King's College London) , Marie O. Y. Pang (King’s College London; Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma) , Tom Ceska (UCB Pharma) , Andrew J. Beavil (King’s College London; Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma) , Graham Craggs (UCB Pharma) , Marta Westwood (UCB Pharma) , Alistair J. Henry (UCB Pharma) , James M. Mcdonnell (King’s College London; Medical Research Council & Asthma UK Centre in Allergic Mechanisms of Asthma) , Brian J. Sutton (King's College London)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Biological Chemistry

State: Published (Approved)
Published: April 2017
Diamond Proposal Number(s): 1220

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.

Journal Keywords: allergy; allosteric regulation; antibody; immunoglobulin E (IgE); X-ray crystallography; omalizumab

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography

Documents:
jbc.M117.776476.full.pdf

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