Crystal structure of the human IgG4 CH3 dimer reveals the role of Arg409 in the mechanism of Fab-arm exchange

► The crystal structure of the IgG4 CH3 domain dimer has been solved at 1.8 Å resolution. ► The effect of Arg409 on the IgG4 CH3 interface is revealed by comparison with IgG1. ► Arg409 disrupts a network of water molecules that is conserved in IgG1. ► Arg409 weakens the interaction at the CH3 interface. ► The mechanism by which Arg409 predisposes human IgG4 to Fab-arm exchange is proposed.