The structure of a human type III Fc gamma receptor in complex with Fc

Fc gamma receptors mediate antibody-dependent inflammatory responses and cy totoxicity as well as certain autoimmune dysfunctions. Here we report the c rystal structure of a human Fc receptor (Fc gamma RIIIB) in complex with an Fc fragment of human IgG1 determined from orthorhombic and hexagonal cryst al forms at 3.0- and 3.5-Angstrom resolution, respectively. The refined str uctures from the two crystal forms are nearly identical with no significant discrepancies between the coordinates. Regions of the C-terminal domain of Fc gamma RIII, including the BC, C'E, FG loops, and the C' beta -strand, b ind asymmetrically to the lower hinge region, residues Leu(234)-Pro(238), O f both Fe chains creating a 1:1 receptor-ligand stoichiometry. Minor confor mational changes are observed in both the receptor and Fc upon complex form ation. Hydrophobic residues, hydrogen bonds, and salt bridges are distribut ed throughout the receptor le interface. Sequence comparisons of the recept or-ligand interface residues suggest a conserved binding mode common to all members of immunoglobulin-like Fc receptors, Structural comparison between Fc gamma RIII.Fc and Fc epsilon RI.Fc complexes highlights the differences in ligand recognition between the high and low affinity receptors, Althoug h not in direct contact with the receptor, the carbohydrate attached to the conserved glycosylation residue Asn(297) On Fc may stabilize the conformat ion of the receptor-binding epitope on Fc. An antibody-Fc gamma RIII model suggests two possible ligand-induced receptor aggregations.