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Structural and Functional Analysis of a β<sub>2</sub>-Adrenergic Receptor Complex with GRK5
Komolov, Konstantin E.,Du, Yang,Duc, Nguyen Minh,Betz, Robin M.,Rodrigues, Joã,o P.G.L.M.,Leib, Ryan D.,Patra, Dhabaleswar,Skiniotis, Georgios,Adams, Christopher M.,Dror, Ron O.,Chung, Ka Young Cell Press 2017 Cell Vol. No.
<P><B>Summary</B></P> <P>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 β<SUB>2</SUB>-adrenergic receptor (β<SUB>2</SUB>AR). 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 β<SUB>2</SUB>AR 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.</P> <P><B>PaperClip</B></P> <P>Display Omitted</P> <P><B>Highlights</B></P> <P> <UL> <LI> GRK5-β<SUB>2</SUB>AR binding is enhanced by receptor and kinase ligands and acidic lipids </LI> <LI> GRK5 binding to the β<SUB>2</SUB>AR involves a multi-site interaction </LI> <LI> Receptor binding triggers substantial conformational changes in GRK5 </LI> <LI> RH/catalytic domain separation in GRK5 is essential for receptor phosphorylation </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>