Document Type
Article
Publication Date
4-20-2017
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.
Recommended Citation
Komolov, Konstantin E.; Du, Yang; Duc, Nguyen Minh; Betz, Robin M.; Rodrigues, João P.G.L.M.; Leib, Ryan D.; Patra, Dhabaleswar; Skiniotis, Georgios; Adams, Christopher M.; Dror, Ron O.; Chung, Ka Young; Kobilka, Brian K.; and Benovic, Jeffrey L., "Structural and Functional Analysis of a β2-Adrenergic Receptor Complex with GRK5." (2017). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 118.
https://jdc.jefferson.edu/bmpfp/118
PubMed ID
28431242
Comments
This article has been peer reviewed. It is the authors' final version prior to publication in Cell
Volume 169, Issue 3, April 2017, Pages 407-421.e16.
The published version is available at DOI: 10.1016/j.cell.2017.03.047 Copyright © Elsevier/Cell Press