SUMMARY G protein-coupled receptors (GPCRs) mediate diverse signaling in part through interaction with arrestins, whose binding promotes receptor internalization and signaling through G protein-independent pathways. High-affinity arrestin binding requires receptor phosphorylation, often at the receptor’s C-terminal tail. Here we report an X-ray free electron laser (XFEL) crystal structure of the rhodopsin–arrestin complex, in which the phosphorylated C-terminus of rhodopsin forms an extended intermolecular β-sheet with the N-terminal β-strands of arrestin. Phosphorylation was detected at rhodopsin C-terminal tail residues T336 and S338. These two phospho-residues, together with E341, form an extensive network of electrostatic interactions with three positively charged pockets in arrestin in a mode that resembles binding of the phosphorylated vasopressin-2 receptor tail to β-arrestin-1. Based on these observations, we derived and validated a set of phosphorylation codes that serve as a common mechanism for phosphorylation-dependent recruitment of arrestins by GPCRs.

provinces in China announced the public health emergency. Psychological distress in the general population has been reported in China during the COVID-19 quarantine [1]. The healthcare system in Wuhan was quickly overwhelmed as tens of thousands of people with flu-like symptoms swarmed the hospitals. Frontline healthcare workers (HCWs) in Wuhan have been under tremendous pressure and risk of contracting COVID-19 since the beginning of the quarantine. As of February 12, 2020, 21,569 HCWs from other cities in China have been deployed to support emergency response efforts in Wuhan [2], while 1716 HCWs have contracted COVID-19 and 5 have died [3]. Two nurses Note. * p < .05, ** p < .01, *** p < .001.

G-protein-coupled receptors comprise the largest family of mammalian transmembrane receptors. They mediate numerous cellular pathways by coupling with downstream signalling transducers, including the hetrotrimeric G proteins G (stimulatory) and G (inhibitory) and several arrestin proteins. The structural mechanisms that define how G-protein-coupled receptors selectively couple to a specific type of G protein or arrestin remain unknown. Here, using cryo-electron microscopy, we show that the major interactions between activated rhodopsin and G are mediated by the C-terminal helix of the G α-subunit, which is wedged into the cytoplasmic cavity of the transmembrane helix bundle and directly contacts the amino terminus of helix 8 of rhodopsin. Structural comparisons of inactive, G-bound and arrestin-bound forms of rhodopsin with inactive and G-bound forms of the β-adrenergic receptor provide a foundation to understand the unique structural signatures that are associated with the recognition of G, G and arrestin by activated G-protein-coupled receptors.