Comprehensive Analysis of the Role of Arrestin Residues in Receptor Binding

The molecular mechanism of arrestin–G protein-coupled receptor (GPCR ) complex formation has been analyzed using inter alia spectroscopic, mutagenesis and structure determination methods. The latest crystal structure elucidating one conformation of the rhodopsin -bound arrestin-1 complex confirmed our structural model of an overall complex conformation and experimentally based assumptions about single residues located at the direct binding interface. Comprehensive analyses of single amino acid contributions in arrestin-1 and other methodologies expand our knowledge of structure–function relationships for receptor recognition and arrestin–GPCR complex formation. With a lot of progress made in the last few years, we review most recent literature covering the roles of essential arrestin-1 residues for pre-activation, receptor recognition and receptor binding. Mechanistic understanding of these processes at the atomic level is key for the identification of receptor conformations triggering given signaling pathways and the creation of novel tools for biased ligand drug discovery.