Elucidating structural and molecular mechanisms of β-arrestin-biased agonism at GPCRs via MS-based proteomics

作者：Xiao, Kunhong^*; Sun, Jinpeng

来源：Cellular Signalling, 2017, 41: 56-64.

DOI：10.1016/j.cellsig.2017.09.013

• 7TMR
• GPCR
• Arrestin
• beta-Arrestin
• Biased agonism
• Biased agonist
• Mass spectrometry
• Proteomics
• Pharmacology
• Drug discovery

The discovery of beta-arrestin-dependent GPCR signaling has led to an exciting new field in GPCR pharmacology: to develop "biased agonists" that can selectively target a specific downstream signaling pathway that elicits beneficial therapeutic effects without activating other pathways that elicit negative side effects. This new trend in GPCR drug discovery requires us to understand the structural and molecular mechanisms of beta-arrestin-biased agonism, which largely remain unclear. We have used cutting-edge mass spectrometry (MS)-based proteomics, combined with systems, chemical and structural biology to study protein function, macromolecular interaction, protein expression and posttranslational modifications in the beta-arrestin-dependent GPCR signaling. These high throughput proteomic studies have provided a systems view of beta-arrestin-biased agonism from several perspectives: distinct receptor phosphorylation barcode, multiple receptor conformations, distinct beta-arrestin conformations, and ligand-specific signaling. The information obtained from these studies offers new insights into the molecular basis of GPCR regulation by beta-arrestin and provides a potential platform for developing novel therapeutic interventions through GPCRs.

• 出版日期2017-12-15
• 单位山东大学