Understanding the GPCR biased signaling through G protein and arrestin complex structures

•Recent advance in structural studies of GPCR signaling complexes is reviewed.•Agonist-binding induces the opening of TM6 and the intracellular pocket of a GPCR.•An open intracellular pocket is required for GPCRs to recruit signaling partners.•Arrestin recruitment requires a phosphorylated receptor C-terminal tail.•Biased ligands induce GPCR conformations for binding specific signaling partners. G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and are important drug targets for many human diseases. The determination of the 3-D structure of GPCRs and their signaling complexes has promoted our understanding of GPCR biology and provided templates for structure-based drug discovery. In this review, we focus on the recent structure work on GPCR signaling complexes, the β2-adrenoreceptor-Gs and the rhodopsin-arrestin complexes in particular, and highlight the structural features of GPCR complexes involved in G protein- and arrestin-mediated signal transduction. The crystal structures reveal distinct structural mechanisms by which GPCRs recruit a G protein and an arrestin. A comparison of the two complex structures provides insight into the molecular mechanism of functionally selective GPCR signaling, and a structural basis for the discovery of G protein- and arrestin-biased treatments of human diseases related to GPCR signal transduction.