Crystal structure at 2.8 Å of an FcRn/heterodimeric Fc complex:: Mechanism of pH-dependent binding

The neonatal Fc receptor (FcRn) transports immunoglobulin G (IgG) across epithelia, binding IgG in acidic vesicles (pH less than or equal to 6.5) and releasing IgG in the blood at pH 7.4. Well-ordered FcRn/Fc crystals are prevented by the formation of oligomeric ribbons of FcRn dimers bridged by Fc homodimers, thus we crystallized a 1:1 complex between rat FcRn and a heterodimeric Fc containing only one FcRn binding site. The 2.8 Angstrom complex structure demonstrates that FcRn uses its alpha2 and beta2-microglobulin domains and carbohydrate to interact with the Fc C(gamma)2-C(gamma)3 interface. The structure reveals conformational changes in Fc and three titratable salt bridges that confer pH-dependent binding, and can be used to guide rational design of therapeutic IgGs with longer serum half-lives.