Structure of the neurotensin receptor 1 in complex with β-arrestin 1

Nature. 2020 Mar;579(7798):303-308. doi: 10.1038/s41586-020-1953-1. Epub 2020 Jan 16.

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 detailing the interactions between GPCRs and G proteins, less is known about how arrestins engage GPCRs. Here we report a cryo-electron microscopy structure of full-length human neurotensin receptor 1 (NTSR1) in complex with truncated human β-arrestin 1 (βarr1(ΔCT)). We find that phosphorylation of NTSR1 is critical for the formation of a stable complex with βarr1(ΔCT), and identify phosphorylated sites in both the third intracellular loop and the C terminus that may promote this interaction. In addition, we observe a phosphatidylinositol-4,5-bisphosphate molecule forming a bridge between the membrane side of NTSR1 transmembrane segments 1 and 4 and the C-lobe of arrestin. Compared with a structure of a rhodopsin-arrestin-1 complex, in our structure arrestin is rotated by approximately 85° relative to the receptor. These findings highlight both conserved aspects and plasticity among arrestin-receptor interactions.

MeSH terms

  • Cryoelectron Microscopy
  • Humans
  • Models, Molecular*
  • Phosphorylation
  • Protein Stability
  • Protein Structure, Quaternary
  • Receptors, Neurotensin / chemistry*
  • Receptors, Neurotensin / metabolism
  • beta-Arrestin 1 / chemistry*
  • beta-Arrestin 1 / metabolism

Substances

  • Receptors, Neurotensin
  • beta-Arrestin 1
  • neurotensin type 1 receptor