30AF

Complex between IgE-Fc and anti-IgE Fab aeFab98

Summary for 30AF

• Entry DOI: 10.2210/pdb30af/pdb
• Descriptor: Isoform 1 of Immunoglobulin heavy constant epsilon, aeFab98 heavy chain, aeFab98 light chain, ... (9 entities in total)
• Functional Keywords: antibody, ige, fab, complex, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 121399.28

Authors

Davies, A.M.,Drinkwater, N.,Beavil, A.J.,O'Dowd, V.,Lightwood, D.,Ceska, T.,Henry, A.J.,Sutton, B.J.,McDonnell, J.M. (deposition date: 2026-04-16, release date: 2026-09-02, Last modification date: 2026-09-16)

Primary citation

Davies, A.M.,Drinkwater, N.,Beavil, A.J.,O'Dowd, V.,Lightwood, D.,Ceska, T.,Henry, A.J.,Sutton, B.J.,McDonnell, J.M.
Antibodies targeting a shared epitope exploit IgE allostery to drive distinct functional outcomes.
Proc.Natl.Acad.Sci.USA, 123:e2613091123-e2613091123, 2026

PubMed Abstract: The Fc region of immunoglobulin E (IgE-Fc) is an important therapeutic target due to the antibody's critical role in allergic disorders through interactions with high-affinity (FcεRI) 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-function 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 Cε2 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 FcεRI 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., "same epitope, same functional outcome," and highlights the importance of accounting for both the target's 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.

PubMed: 42709784
DOI: 10.1073/pnas.2613091123

Experimental method

X-RAY DIFFRACTION (2.4 Å)