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U.S.A."],"published-print":{"date-parts":[[2026,9,15]]},"abstract":"<jats:p>The Fc region of immunoglobulin E (IgE-Fc) is an important therapeutic target due to the antibody\u2019s critical role in allergic disorders through interactions with high-affinity (Fc\u03b5RI) and low-affinity (CD23) receptors. IgE-Fc is known to be conformationally flexible, undergoing large-scale structural changes that modulate receptor binding and downstream biological functions. The mechanistic basis for how ligands induce these allosteric changes is not fully understood. In this study, we investigate structure\u2013function relationships of IgE by characterizing four closely related anti-IgE-Fc Fab fragments with highly conserved sequences that recognize a shared epitope at the base of the C\u03b52 domain. Despite their sequence similarity, these Fabs exhibit markedly different binding characteristics, stoichiometries, and functional activities. Furthermore, the crystal structures of these four Fab complexes reveal that the bound IgE-Fc adopts a wide range of conformations. These structural differences directly dictate the functional outcomes, ranging from conformations that facilitate Fc\u03b5RI binding to those that prevent or destabilize receptor interaction. Our findings demonstrate that highly similar antibodies binding to the same epitope on a protein that exhibits significant conformational plasticity can elicit distinct and divergent functional outcomes. This work challenges the conventional antibody discovery paradigm, i.e., \u201csame epitope, same functional outcome,\u201d and highlights the importance of accounting for both the target\u2019s structural flexibility and the resulting functional diversity within antibody selection strategies. This is especially critical when targeting dynamic proteins where allosteric mechanisms are fundamental to function.<\/jats:p>","DOI":"10.1073\/pnas.2613091123","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T17:47:37Z","timestamp":1788889657000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Antibodies targeting a shared epitope exploit IgE allostery to drive distinct functional outcomes"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1498-1594","authenticated-orcid":false,"given":"Anna M.","family":"Davies","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0220mzb33","id-type":"ROR","asserted-by":"publisher"}],"name":"Randall Centre for Cell and Molecular Biophysics, King\u2019s College London, New Hunt\u2019s House","place":["London, United 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