Synthesis and incorporation into cyclic peptides of tolan amino acids and their hydrogenated congeners: construction of an array of A–B-loop mimetics of the Cε3 domain of human IgE

The disruption of the human immunolobulin E–high affinity receptor I (IgE–FcεRI) protein–protein interaction (PPI) is a validated strategy for the development of anti asthma therapeutics. Here, we describe the synthesis of an array of conformationally constrained cyclic peptides based on an epitope of the A–B loop within the Cε3 domain of IgE. The peptides contain various tolan (i.e., 1,2-biarylethyne) amino acids and their fully and partially hydrogenated congeners as conformational constraints. Modest antagonist activity (IC50 660 μM) is displayed by the peptide containing a 2,2′-tolan, which is the one predicted by molecular modeling to best mimic the conformation of the native A–B loop epitope in IgE

Synthesis and Incorporation into Cyclic Peptides of Tolan Amino Acids and Their Hydrogenated Congeners: Construction of an Array of A–B-loop Mimetics of the Cε3 Domain of Human IgE

The disruption of the human immunolobulin E–high affinity receptor I (IgE–FcεRI) protein–protein interaction (PPI) is a validated strategy for the development of anti asthma therapeutics. Here, we describe the synthesis of an array of conformationally constrained cyclic peptides based on an epitope of the A–B loop within the Cε3 domain of IgE. The peptides contain various tolan (i.e., 1,2-biarylethyne) amino acids and their fully and partially hydrogenated congeners as conformational constraints. Modest antagonist activity (IC₅₀ ∼660 μM) is displayed by the peptide containing a 2,2′-tolan, which is the one predicted by molecular modeling to best mimic the conformation of the native A–B loop epitope in IgE

The crystal structure of rabbit IgG-Fc

International audienceWe report the structure of the Fc fragment of rabbit IgG at 1.95 angstrom resolution. Rabbit IgG was the molecule for which Porter established the four-chain, Y-shaped structure of the antibody molecule, and crystals of the Fc (“Fragment crystallisable”) were first reported almost 50 years ago in this journal (Porter R.R., 1959, Biochem. J., 73, 119-126). This high-resolution analysis, apparently of the same crystal form, reveals several features of IgG-Fc structure that have not previously been described. More of the lower hinge region is visible in this structure than in others, demonstrating not only the acute bend in the IgG molecule that this region can mediate, as seen in receptor complexes, but also that this region has a tendency to adopt a bent structure even in the absence of receptor. As observed in other IgG-Fc structures, the Cγ2 domains display greater mobility/disorder within the crystals than the Cγ3 domains; unexpectedly the structure reveals partial cleavage of both Cγ2 intra-domain disulphide bonds, while an alternative conformation for one of the cysteine residues in the intact bridge within the more ordered Cγ3 domains is observed. The N-linked oligosaccharide chains at Asn-297 are well-defined and reveal two alternative conformations for the galactose units on each of α(1-6) linked branches. The presence of this galactose unit is important for stabilising the structure of the entire branched carbohydrate chain, and its absence correlates with severity of autoimmune conditions such as rheumatoid arthritis in both human clinical studies and in a rabbit model of the disease. Rabbit IgG, through this high-resolution structure of its Fc region, thus continues to offer new insights into antibody structure

Conformational changes in IgE contribute to its uniquely slow dissociation rate from receptor FcɛRI

Among antibody classes, IgE has a uniquely slow dissociation rate from, and high affinity for, its cell surface receptor FcI RI. We show the structural basis for these key determinants of the ability of IgE to mediate allergic hypersensitivity through the 3.4-Ã.-resolution crystal structure of human IgE-Fc (consisting of the CI 2, CI 3 and CI 4 domains) bound to the extracellular domains of the FcI RI Î ± chain. Comparison with the structure of free IgE-Fc (reported here at a resolution of 1.9 Ã.) shows that the antibody, which has a compact, bent structure before receptor engagement, becomes even more acutely bent in the complex. Thermodynamic analysis indicates that the interaction is entropically driven, which explains how the noncontacting CI 2 domains, in place of the flexible hinge region of IgG antibodies, contribute together with the conformational changes to the unique binding properties of IgE. © 2011 Nature America, Inc. All rights reserved