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Mutagenesis studies indicate overlapping Fc\u03b5RI and omalizumab-binding sites in the C\u03b53 domain, but crystallographic studies show Fc\u03b5RI and CD23-binding sites that are far apart, so how can omalizumab block IgE from binding both receptors? We report a 2.42-\u00c5 omalizumab-Fab structure, a docked IgE-Fc\/omalizumab-Fab structure consistent with available experimental data and the free energy contributions of IgE residues to binding omalizumab, CD23 and Fc\u03b5RI. These results provide a structural and physical basis as to why omalizumab cannot bind receptor-bound IgE and why omalizumab-bound IgE cannot bind to CD23\/Fc\u03b5RI. 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