5HYS

Structure of IgE complexed with omalizumab

Summary for 5HYS

• Entry DOI: 10.2210/pdb5hys/pdb
• Descriptor: Epididymis luminal protein 214, Uncharacterized protein, Ig epsilon chain C region, ... (6 entities in total)
• Functional Keywords: immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 12
• Total formula weight: 301108.26

Authors

Pennington, L.F.,Tarchevskaya, S.S.,Sathiyamoorthy, K.,Jardetzky, T.S. (deposition date: 2016-02-01, release date: 2016-06-01, Last modification date: 2024-12-25)

Primary citation

Pennington, L.F.,Tarchevskaya, S.,Brigger, D.,Sathiyamoorthy, K.,Graham, M.T.,Nadeau, K.C.,Eggel, A.,Jardetzky, T.S.
Structural basis of omalizumab therapy and omalizumab-mediated IgE exchange.
Nat Commun, 7:11610-11610, 2016

PubMed Abstract: Omalizumab is a widely used therapeutic anti-IgE antibody. Here we report the crystal structure of the omalizumab-Fab in complex with an IgE-Fc fragment. This structure reveals the mechanism of omalizumab-mediated inhibition of IgE interactions with both high- and low-affinity IgE receptors, and explains why omalizumab selectively binds free IgE. The structure of the complex also provides mechanistic insight into a class of disruptive IgE inhibitors that accelerate the dissociation of the high-affinity IgE receptor from IgE. We use this structural data to generate a mutant IgE-Fc fragment that is resistant to omalizumab binding. Treatment with this omalizumab-resistant IgE-Fc fragment, in combination with omalizumab, promotes the exchange of cell-bound full-length IgE with omalizumab-resistant IgE-Fc fragments on human basophils. This combination treatment also blocks basophil activation more efficiently than either agent alone, providing a novel approach to probe regulatory mechanisms underlying IgE hypersensitivity with implications for therapeutic interventions.

PubMed: 27194387
DOI: 10.1038/ncomms11610

Experimental method

X-RAY DIFFRACTION (2.5 Å)