Structural basis for binding of human IgG1 to its high-affinity human receptor FcγRI

Cell-surface Fc gamma receptors mediate innate and adaptive immune responses. Human Fc gamma receptor I (hFc gamma RI) binds IgGs with high affinity and is the only Fc gamma receptor that can effectively capture monomeric IgGs. However, the molecular basis of hFc gamma RI's interaction with Fc has not been determined, limiting our understanding of this major immune receptor. Here we report the crystal structure of a complex between hFc gamma RI and human Fc, at 1.80 angstrom resolution, revealing an unique hydrophobic pocket at the surface of hFc gamma RI perfectly suited for residue Leu235 of Fc, which explains the high affinity of this complex. Structural, kinetic and thermodynamic data demonstrate that the binding mechanism is governed by a combination of non-covalent interactions, bridging water molecules and the dynamic features of Fc. In addition, the hinge region of hFc gamma RI-bound Fc adopts a straight conformation, potentially orienting the Fab moiety. These findings will stimulate the development of novel therapeutic strategies involving hFc gamma RI.