Structural highlights
Publication Abstract from PubMedImmunoglobulin E and its interactions with receptors FcRI and CD23 play a central role in allergic disease. Omalizumab, a clinically-approved therapeutic antibody, inhibits the interaction between IgE and FcRI, 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 C3 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 C3 domains that inhibit the interaction with FcRI. CD23 binding is inhibited sterically due to overlapping binding sites on each C3 domain. Studies of omalizumab Fab binding in solution demonstrate the allosteric basis for FcRI inhibition and, together with the structure, reveal how omalizumab may accelerate dissociation of receptor-bound IgE from FcRI, exploiting the intrinsic flexibility and allosteric potential of IgE. Allosteric mechanism of action of the therapeutic anti-IgE antibody omalizumab.,Davies AM, Allan EG, Keeble AH, Delgado J, Cossins BP, Mitropoulou AN, Pang MOY, Ceska T, Beavil AJ, Craggs G, Westwood M, Henry AJ, McDonnell JM, Sutton BJ J Biol Chem. 2017 Apr 24. pii: jbc.M117.776476. doi: 10.1074/jbc.M117.776476. PMID:28438838[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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