Abstract

Arrestin proteins bind to active, phosphorylated G-protein-coupled receptors (GPCRs), thereby preventing G-protein coupling, triggering receptor internalization, and affecting various downstream signalling pathways1,2. Although there is a wealth of structural information delineating the interactions between GPCRs and G proteins, less is known about how arrestins engage GPCRs. Here we report a cryo-EM structure of full-length human neurotensin receptor 1 (NTSR1) in complex with truncated human ß-arrestin 1 (ßarr1?CT). We found that phosphorylation of NTSR1 was critical for obtaining a stable complex with ßarr1?CT, and identified phosphorylated sites in both the third intracellular loop and the C terminus that may promote this interaction. In addition, we observed a phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) molecule forming a bridge between the membrane side of NTSR1 transmembrane segments 1 and 4 and the C-lobe of arrestin. Compared to a structure of rhodopsin-arrestin-1, our structure displays an approximately 85° rotation of arrestin relative to the receptor. These findings highlight both conserved aspects but also the plasticity of arrestin-receptor interactions.

View details for DOI 10.1038/s41586-020-1953-1

View details for PubMedID 31945771