期刊
CELL
卷 169, 期 3, 页码 407-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2017.03.047
关键词
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资金
- NIH [R01GM068857, P01HL114471, R01GM083118, R01NS028571]
- Mathers Foundation
- Stanford University Terman Faculty Fellowship
- National Research Foundation of Korea - Korean government [NFR-2015R1A1A1A05027473, NRF-2012R1A5A2A28671860]
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 crosslinking, hydrogen-deuterium exchange mass spectrometry (MS), electron microscopy, mutagenesis, molecular dynamics simulations, and computational docking to analyze GRK5 interaction with the b2-adrenergic receptor (beta(2)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 beta(2)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.
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