Structural and Functional Analysis of a β2-Adrenergic Receptor Complex with GRK5

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Abstract

The phosphorylation of agonist-occupied G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) functions to turn off G-protein signaling and turn on arrestin-mediated signaling. While a structural understanding of GPCR/G-protein and GPCR/arrestin complexes has emerged in recent years, the molecular architecture of a GPCR/GRK complex remains poorly defined. We used a comprehensive integrated approach of cross-linking, hydrogen-deuterium exchange mass spectrometry (MS), electron microscopy, mutagenesis, molecular dynamics simulations, and computational docking to analyze GRK5 interaction with the β2-adrenergic receptor (β2AR). These studies revealed a dynamic mechanism of complex formation that involves large conformational changes in the GRK5 RH/catalytic domain interface upon receptor binding. These changes facilitate contacts between intracellular loops 2 and 3 and the C terminus of the β2AR with the GRK5 RH bundle subdomain, membrane-binding surface, and kinase catalytic cleft, respectively. These studies significantly contribute to our understanding of the mechanism by which GRKs regulate the function of activated GPCRs. PaperClip

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Komolov, K. E., Du, Y., Duc, N. M., Betz, R. M., Rodrigues, J. P. G. L. M., Leib, R. D., … Benovic, J. L. (2017). Structural and Functional Analysis of a β2-Adrenergic Receptor Complex with GRK5. Cell, 169(3), 407-421.e16. https://doi.org/10.1016/j.cell.2017.03.047

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