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

G protein-coupled receptors (GPCRs) recruit beta-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 beta-arrestins but not G proteins, making them a model system for investigating the structural basis of beta-arrestin recruitment. Here, we performed nuclear magnetic resonance (NMR) experiments on (CH3)-C-13-epsilon-methionine-labeled ACKR3, revealing that beta-arrestin recruitment is associated with conformational exchange at key regions of the extracellular ligand-binding pocket and intracellular beta-arrestin-coupling region. NMR studies of ACKR3 mutants defective in beta-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 beta-arrestin recruitment by tuning receptor dynamics at intracellular and extracellular regions.

Automated summary

NMR experiments on ACKR3 revealed that the recruitment of beta-arrestins is associated with conformational exchange at key regions of the receptor, and identified an allosteric hub in the core receptor that coordinates transitions among different conformational states, guiding beta-arrestin recruitment.