The Structure of a Human Type III Fcγ Receptor in Complex with Fc

Abstract

Fcγ receptors mediate antibody-dependent inflammatory responses and cytotoxicity as well as certain autoimmune dysfunctions. Here we report the crystal structure of a human Fc receptor (FcγRIIIB) in complex with an Fc fragment of human IgG1 determined from orthorhombic and hexagonal crystal forms at 3.0- and 3.5-Å resolution, respectively. The refined structures from the two crystal forms are nearly identical with no significant discrepancies between the coordinates. Regions of the C-terminal domain of FcγRIII, including the BC, C′E, FG loops, and the C′ β-strand, bind asymmetrically to the lower hinge region, residues Leu234-Pro 238, of both Fc chains creating a 1:1 receptor-ligand stoichiometry. Minor conformational changes are observed in both the receptor and Fc upon complex formation. Hydrophobic residues, hydrogen bonds, and salt bridges are distributed throughout the receptor′Fc interface. Sequence comparisons of the receptor-ligand interface residues suggest a conserved binding mode common to all members of immunoglobulin-like Fc receptors. Structural comparison between FcγRIII·Fc and FcεRI·Fc complexes highlights the differences in ligand recognition between the high and low affinity receptors. Although not in direct contact with the receptor, the carbohydrate attached to the conserved glycosylation residue Asn297 on Fc may stabilize the conformation of the receptor-binding epitope on Fc. An antibody-FcγRIII model suggests two possible ligand-induced receptor aggregations.