Crystal Structure of Fcγ Receptor I and Its Implication in High Affinity γ-Immunoglobulin Binding

Fc gamma receptors (Fc gamma Rs) play critical roles in humoral and cellular immune responses through interactions with the Fc region of immunoglobulin G (IgG). Among them, Fc gamma RI is the only high affinity receptor for IgG and thus is a potential target for immunotherapy. Here we report the first crystal structure of an Fc gamma RI with all three extracellular Ig-like domains (designated as D1, D2, and D3). The structure shows that, first, Fc gamma RI has an acute D1-D2 hinge angle similar to that of Fc epsilon RI but much smaller than those observed in the low affinity Fc gamma receptors. Second, the D3 domain of Fc gamma RI is positioned away from the putative IgG binding site on the receptor and is thus unlikely to make direct contacts with Fc. Third, the replacement of Fc gamma RIII FG-loop ((171)LVGSKNV(177)) with that of Fc gamma RI ((171)MGKHRY(176)) resulted in a 15-fold increase in IgG, binding affinity, whereas a valine insertion in the Fc gamma RI FG-loop ((171)MVGKHRY(177)) abolished the affinity enhancement. Thus, the Fc gamma RI FG-loop with its conserved one-residue deletion is critical to the high affinity IgG binding. The structural results support Fc gamma RI binding to IgG in a similar mode as its low affinity counterparts. Taken together, our study suggests a molecular mechanism for the high affinity IgG recognition by Fc gamma RI and provides a structural basis for understanding its physiological function and its therapeutic implication in treating autoimmune diseases.