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

Cell-surface Fcg receptors mediate innate and adaptive immune responses. Human Fcg receptor I (hFcgRI) binds IgGs with high affinity and is the only Fcg receptor that can effectively capture monomeric IgGs. However, the molecular basis of hFcgRI’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 hFcgRI and human Fc, at 1.80Å resolution, revealing an unique hydrophobic pocket at the surface of hFcgRI 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 hFcgRI-bound Fc adopts a straight conformation, potentially orienting the Fab moiety. These findings will stimulate the development of novel therapeutic strategies involving hFcgRI