Recognition of IgG by Fc gamma receptor - The role of Fc glycosylation andthe binding of peptide inhibitors

Recently determined crystal structures of the complex between immunoglobuli n constant regions (Fc) and their Fc-respective receptors (FcR) have reveal ed the detailed molecular interactions of this receptor-ligand pair. Of par ticular interest is the contribution of a glycosylation at Asn(297) of the C(H)2 domain of IgG to receptor recognition. The carbohydrate moieties are found outside the receptor Fe interface in all receptor Fe complex structur es. To understand the role of glycosylation in FcR recognition, the recepto r affinities of a deglycosylated IgG1 and its Fc fragment were determined b y solution binding studies using surface plasmon resonance. The removal of carbohydrates resulted in a non-detectable receptor binding to the Fc alone and a 15- to 20-fold reduction of the receptor binding to IgG1, suggesting that the carbohydrates are important in the function of the Fc gamma RIII. Structurally, the carbohydrates attached to Asn(297) fill the cavity betwe en the C(H)2 domains of Fc functioning equivalently as a hydrophobic core. This may stabilize a favorable lower hinge conformation for the receptor bi nding, The structure of the complex also revealed the dominance of the lowe r hinge region in receptor.Fc recognition, To evaluate the potential of des igning small molecular ligands to inhibit the receptor function, four lower hinge peptides were investigated for their ability to bind to the receptor Fc gamma RIII, These peptides bind specifically to Fc gamma RIII with affi nities 20- to 100-fold lower than IgG1 and are able to compete with Fc in r eceptor binding. The results of peptide binding illustrate new ways of desi gning therapeutic compounds to block Fc receptor activation.