The molecular basis of IgG and FcγR interactions
The extracellular regions of the FcγR are structurally similar. Each low‐affinity FcγR has two ectodomains, whereas the high‐affinity FcγRI has a third domain but this is not directly involved in IgG binding.62
The interaction between the IgG subclasses and the FcγR is most comprehensively defined for human IgG1 by both X‐ray crystallographic7, 62, 63 and mutagenesis structure/function analyses.64, 65, 66 These studies defined key regions of the IgG sequence required for interaction with their FcγRs.
Crystallographic analyses of the human IgG1‐Fc complexed with FcγRI, FcγRII or FcγRIII show that these interactions are similar in topology, and asymmetric in nature. The second extracellular domain of the FcγR inserts between the two heavy chains. Here it makes contacts with the lower hinge of both H chains and with residues of the adjacent BC loop of one CH2 domain and the FG loop of the other. The N‐linked glycan at asparagine 297 (N297) of the heavy chain is essential for the structural integrity of the IgG‐Fc by affecting the spacing and conformation of the CH2 domains. Indeed, its removal ablates FcγR binding.67 Of particular relevance to therapeutic mAb development is that the normal low‐affinity IgG interaction with FcγRIIIa is profoundly increased by the removal of the core fucose from the N297 Fc oligosaccharide.68
No crystallographic data are available for IgG2 or IgG4 Fc in complex with FcγR, but mutagenesis studies of the Fc and the FcγR revealed general similarity, but with critical differences, in the interaction of these subclasses with their cognate FcγR.