Conformational selection guides β-arrestin recruitment at a biased G protein–coupled receptor
Andrew B. Kleist, Shawn Jenjak, Andrija Sente, Lauren J. Laskowski, Martyna Szpakowska, Maggie M. Calkins, Emilie I. Anderson, Lisa McNally, Raimond Heukers, Vladimir Bobkov, Francis C. Peterson, Monica A. Thomas, Andy Chevigné, Martine J. Smit, John D. McCorvy, M. Madan Babu, Brian F. Volkman
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 13 CH 3 -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.