The majority of hormones and neurotransmitters communicate information to cells via G protein-coupled receptors (GPCRs). The large number of biological functions they control also makes these membrane receptors one of the most prominent families of pharmacological targets in biomedicine. GPCRs exhibit complex signaling behaviors. Indeed, a single receptor can activate both G protein-dependent and G protein-independent pathways. The latter result from the coupling of the receptor to a major family of signaling proteins, arrestins. Although arrestin-dependent signaling is a major component of GPCR functioning, we are just beginning to grasp its mechanistic bases, even for the best-studied GPCRs. The current model of GPCR:arrestin interaction, the so-called phospho-barcode model, states that, upon activation by their ligand, GPCRs get phosphorylated at different sites on their C-terminal domain, and this impacts on the way arrestin interacts with these regions, in turn affecting its conformation and, ultimately, the intracellular signal arrestin triggers. However, the experimental demonstrations of this mode of functioning are still scarce. Interestingly, the GPCR C-terminal domains appear to present all the structural, dynamic and functional characteristics of intrinsically disorder regions (IDRs), a family of proteins whose specific role in fundamental signaling and regulation processes started to be revealed very recently. In GPCteR, we propose an analysis of the molecular mechanisms underlying arrestin:GPCR interaction, and hence arrestin-dependent signaling, using a combination of state-of-the-art biophysical methods, namely solution-state Nuclear Magnetic Resonance, Small Angle Neutron or X-ray Scattering and fluorescence spectroscopy. These methods will be applied to a full range of model systems of increasing complexity composed of isolated GPCR C-terminal peptides, purified arrestins, and kinases and full-length receptors assembled into membrane-mimicking systems. Three different GPCR systems, the ghrelin, the vasopressin V2 and the B2-adrenergic receptors will be used as models. Besides the fact that these receptors are representative of the two different classes of arrestin binders, they are also important pharmaceutical targets due to their major role in fundamental physiological and patho-physiological processes. We expect these studies to illuminate the structural and dynamic keys required for the interaction of GPCRs with arrestins and, as such, to help us understand how G protein-independent signaling proceeds. This is not of academic interest only as our studies will likely provide also essential information to guide the rational design of peptide mimetics that could interfere with this interaction and thus be used as selective drugs and/or pharmacological tools to only affect receptor:arrestin interaction, to modulate specific signaling cascades, and therefore to impact on a limited set of all the biological effects controlled by GPCRs.