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Structural and Physical Basis for Anti-IgE Therapy.

Wright JD, Chu HM, Huang CH, Ma C, Chang TW, Lim C - Sci Rep (2015)

Bottom Line: Mutagenesis studies indicate overlapping FcεRI and omalizumab-binding sites in the Cε3 domain, but crystallographic studies show FcεRI and CD23-binding sites that are far apart, so how can omalizumab block IgE from binding both receptors?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/FcεRI.They reveal the key IgE residues and their roles in binding omalizumab, CD23, and FcεRI.

View Article: PubMed Central - PubMed

Affiliation: 1] Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan [2] The Genomics Research Center, Academia Sinica 115, Taiwan.

ABSTRACT
Omalizumab, an anti-IgE antibody, used to treat severe allergic asthma and chronic idiopathic urticaria, binds to IgE in blood or membrane-bound on B lymphocytes but not to IgE bound to its high (FcεRI) or low (CD23) affinity receptor. Mutagenesis studies indicate overlapping FcεRI and omalizumab-binding sites in the Cε3 domain, but crystallographic studies show FcεRI and CD23-binding sites that are far apart, so how can omalizumab block IgE from binding both receptors? We report a 2.42-Å 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 FcεRI. 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/FcεRI. They reveal the key IgE residues and their roles in binding omalizumab, CD23, and FcεRI.

No MeSH data available.


Related in: MedlinePlus

Free energy contributions of IgE residues towards binding(a) omalizumab-Fv, (b) CD23, and (c) FcεRI. Residues experimentally implicated in binding omalizumab are labeled.
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f5: Free energy contributions of IgE residues towards binding(a) omalizumab-Fv, (b) CD23, and (c) FcεRI. Residues experimentally implicated in binding omalizumab are labeled.

Mentions: Which residues make the most favorable contributions towards binding omalizumab? To address this question, the binding free energy contribution of each IgE residue was computed using 8,000 conformations sampled from four simulations of the Cε3-4 dimer bound to omalizumab-Fv in explicit water. Although the scheme used to compute the binding free energy cannot yield accurate absolute free energies due to the continuum solvent approximation used to compute the interaction free energy35 (see Methods), it can yield trends in the relative free energy contributions of residues towards binding a given ligand. The free energy contributions of non-interface residues are insignificant, so only those of the interface residues are listed in Supplementary Table 1. Among the IgE interface residues, Ser407, Ala410, Ser411, Lys415, Arg457, Arg465, Met469, and Arg470 make significantly favorable contributions to binding omalizumab (see Fig. 5a). These residues have been implicated in binding omalizumab from site-directed mutagenesis26 except Ala410 and Arg470 whose roles in binding omalizumab have not been experimentally examined. The 462HLP464 motif is also experimentally implicated in binding omalizumab, but its net free energy contribution is relatively small (–2.3 kcal/mol).


Structural and Physical Basis for Anti-IgE Therapy.

Wright JD, Chu HM, Huang CH, Ma C, Chang TW, Lim C - Sci Rep (2015)

Free energy contributions of IgE residues towards binding(a) omalizumab-Fv, (b) CD23, and (c) FcεRI. Residues experimentally implicated in binding omalizumab are labeled.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4481376&req=5

f5: Free energy contributions of IgE residues towards binding(a) omalizumab-Fv, (b) CD23, and (c) FcεRI. Residues experimentally implicated in binding omalizumab are labeled.
Mentions: Which residues make the most favorable contributions towards binding omalizumab? To address this question, the binding free energy contribution of each IgE residue was computed using 8,000 conformations sampled from four simulations of the Cε3-4 dimer bound to omalizumab-Fv in explicit water. Although the scheme used to compute the binding free energy cannot yield accurate absolute free energies due to the continuum solvent approximation used to compute the interaction free energy35 (see Methods), it can yield trends in the relative free energy contributions of residues towards binding a given ligand. The free energy contributions of non-interface residues are insignificant, so only those of the interface residues are listed in Supplementary Table 1. Among the IgE interface residues, Ser407, Ala410, Ser411, Lys415, Arg457, Arg465, Met469, and Arg470 make significantly favorable contributions to binding omalizumab (see Fig. 5a). These residues have been implicated in binding omalizumab from site-directed mutagenesis26 except Ala410 and Arg470 whose roles in binding omalizumab have not been experimentally examined. The 462HLP464 motif is also experimentally implicated in binding omalizumab, but its net free energy contribution is relatively small (–2.3 kcal/mol).

Bottom Line: Mutagenesis studies indicate overlapping FcεRI and omalizumab-binding sites in the Cε3 domain, but crystallographic studies show FcεRI and CD23-binding sites that are far apart, so how can omalizumab block IgE from binding both receptors?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/FcεRI.They reveal the key IgE residues and their roles in binding omalizumab, CD23, and FcεRI.

View Article: PubMed Central - PubMed

Affiliation: 1] Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan [2] The Genomics Research Center, Academia Sinica 115, Taiwan.

ABSTRACT
Omalizumab, an anti-IgE antibody, used to treat severe allergic asthma and chronic idiopathic urticaria, binds to IgE in blood or membrane-bound on B lymphocytes but not to IgE bound to its high (FcεRI) or low (CD23) affinity receptor. Mutagenesis studies indicate overlapping FcεRI and omalizumab-binding sites in the Cε3 domain, but crystallographic studies show FcεRI and CD23-binding sites that are far apart, so how can omalizumab block IgE from binding both receptors? We report a 2.42-Å 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 FcεRI. 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/FcεRI. They reveal the key IgE residues and their roles in binding omalizumab, CD23, and FcεRI.

No MeSH data available.


Related in: MedlinePlus