GPCR activation and GRK2 assembly by a biased intracellular agonist

Nature. 2023 Aug;620(7974):676-681. doi: 10.1038/s41586-023-06395-9. Epub 2023 Aug 2.


Phosphorylation of G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) desensitizes G-protein signalling and promotes arrestin signalling, which is also modulated by biased ligands1-6. The molecular assembly of GRKs on GPCRs and the basis of GRK-mediated biased signalling remain largely unknown owing to the weak GPCR-GRK interactions. Here we report the complex structure of neurotensin receptor 1 (NTSR1) bound to GRK2, Gαq and the arrestin-biased ligand SBI-5537. The density map reveals the arrangement of the intact GRK2 with the receptor, with the N-terminal helix of GRK2 docking into the open cytoplasmic pocket formed by the outward movement of the receptor transmembrane helix 6, analogous to the binding of the G protein to the receptor. SBI-553 binds at the interface between GRK2 and NTSR1 to enhance GRK2 binding. The binding mode of SBI-553 is compatible with arrestin binding but clashes with the binding of Gαq protein, thus providing a mechanism for its arrestin-biased signalling capability. In sum, our structure provides a rational model for understanding the details of GPCR-GRK interactions and GRK2-mediated biased signalling.

MeSH terms

  • Arrestins / metabolism
  • G-Protein-Coupled Receptor Kinase 2* / biosynthesis
  • G-Protein-Coupled Receptor Kinase 2* / chemistry
  • G-Protein-Coupled Receptor Kinase 2* / metabolism
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Ligands
  • Phosphorylation
  • Protein Binding
  • Receptors, G-Protein-Coupled* / metabolism
  • Receptors, Neurotensin / metabolism
  • Signal Transduction*


  • Arrestins
  • Receptors, G-Protein-Coupled
  • G-Protein-Coupled Receptor Kinase 2
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Ligands
  • Receptors, Neurotensin