Conformational selection guides β-arrestin recruitment at a biased G protein-coupled receptor

Science. 2022 Jul 8;377(6602):222-228. doi: 10.1126/science.abj4922. Epub 2022 Jul 7.

Abstract

G protein-coupled receptors (GPCRs) recruit β-arrestins to coordinate diverse cellular processes, but the structural dynamics driving this process are poorly understood. Atypical chemokine receptors (ACKRs) are intrinsically biased GPCRs that engage β-arrestins but not G proteins, making them a model system for investigating the structural basis of β-arrestin recruitment. Here, we performed nuclear magnetic resonance (NMR) experiments on 13CH3-ε-methionine-labeled ACKR3, revealing that β-arrestin recruitment is associated with conformational exchange at key regions of the extracellular ligand-binding pocket and intracellular β-arrestin-coupling region. NMR studies of ACKR3 mutants defective in β-arrestin recruitment identified an allosteric hub in the receptor core that coordinates transitions among heterogeneously populated and selected conformational states. Our data suggest that conformational selection guides β-arrestin recruitment by tuning receptor dynamics at intracellular and extracellular regions.

MeSH terms

  • Allosteric Regulation
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Mutation
  • Protein Binding
  • Protein Conformation
  • Receptors, CXCR* / chemistry
  • Receptors, CXCR* / genetics
  • beta-Arrestins* / chemistry

Substances

  • ACKR3 protein, human
  • Ligands
  • Receptors, CXCR
  • beta-Arrestins