Allosteric mechanism of action of the therapeutic anti-IgE antibody omalizumab
| Autor: | Davies, Anna M., Allan, Elizabeth G., Keeble, Anthony H., Delgado, Jean, Cossins, Benjamin P., Mitropoulou, Alkistis N., Pang, Marie O. Y., Ceska, Tom, Beavil, Andrew J., Craggs, Graham, Westwood, Marta, Henry, Alistair J., McDonnell, James M., Sutton, Brian J. |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Models
Molecular Protein Conformation Recombinant Fusion Proteins Immunology Omalizumab Crystallography X-Ray Protein Refolding Immunoglobulin Fab Fragments antibody Fluorescence Resonance Energy Transfer Humans Point Mutation Protein Interaction Domains and Motifs Anti-Asthmatic Agents Pliability X-ray crystallography immunoglobulin E (IgE) Receptors IgE Immunoglobulin E Surface Plasmon Resonance allergy allosteric regulation Recombinant Proteins Immunoglobulin Fc Fragments Amino Acid Substitution Solubility Allosteric Site |
| Zdroj: | Davies, A M, Allan, E G, Keeble, A H, Delgado, J, Cossins, B P, Mitropoulou, A N, Pang, M O Y, Ceska, T, Beavil, A J, Craggs, G, Westwood, M, Henry, A J, McDonnell, J M & Sutton, B J 2017, ' Allosteric mechanism of action of the therapeutic anti-IgE antibody omalizumab ', Journal of Biological Chemistry, vol. 292, no. 24, pp. 9975–9987 . https://doi.org/10.1074/jbc.M117.776476 The Journal of Biological Chemistry |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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