Structural mechanism of arrestin activation

•Recent crystal structures indicate how arrestin is activated for GPCR binding.•Multiple binding sites for phosphorylated receptor C-terminus exist on arrestin.•Interdomain rotation and finger loop flexibility allow arrestin binding to receptor.•Arrestin and G protein share common binding crevice on the receptor.•Arrestin C-edge functions as membrane anchor.

The large and multifunctional family of G protein-coupled receptors (GPCRs) are regulated by a small family of structurally conserved arrestin proteins. In order to bind an active GPCR, arrestin must first be activated by interaction with the phosphorylated receptor C-terminus. Recent years have witnessed major developments in high-resolution crystal structures of pre-active arrestins and arrestin or arrestin-derived peptides in complex with an active GPCR. Although each structure individually offers only a limited snapshot, taken together and interpreted in light of recent complementary functional data, they offer valuable insight into how arrestin is activated by and couples to a phosphorylated active GPCR.