G protein–coupled receptors (GPCRs) recruit b-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 b-arrestins but not G proteins, making them a model system for investigating the structural basis of b-arrestin recruitment. Here, we performed nuclear magnetic resonance (NMR) experiments on 13CH3-e–methionine–labeled ACKR3, revealing that b-arrestin recruitment is associated with conformational exchange at key regions of the extracellular ligand-binding pocket and intracellular b-arrestin–coupling region. NMR studies of ACKR3 mutants defective in b-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 b-arrestin recruitment by tuning receptor dynamics at intracellular and extracellular regions.
Dynamic control of GPCRs
Arrestins are a group of proteins that regulate signaling through G protein–coupled receptors (GPCRs). They are best known as an off switch in signaling through G proteins, but they also coordinate G protein–independent signaling. Kleist et al. took advantage of an intrinsically β-arrestin–biased GPCR, atypical chemokine receptor 3 (ACKR3), to study β-arrestin recruitment. Nuclear magnetic resonance spectroscopy experiments support a role for conformational selection. The inactive state shows conformational heterogeneity at the ligand-binding pocket. Ligand binding can cause stabilization of an active state that in turn tunes the dynamics at the intracellular region to allow β-arrestin recruitment. —VV
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