A GPCR-G protein-β-arrestin megacomplex enabled by a versatile allosteric modulator

Area of Science:

• Pharmacology
• Molecular Biology
• Drug Discovery

Background:

• G protein-coupled receptors (GPCRs) are crucial drug targets, with about one-third of clinical drugs acting on them.
• GPCR signaling traditionally involves separate G protein and β-arrestin pathways.
• Novel strategies are needed to modulate GPCR activity for unique pharmacological outcomes.

Purpose of the Study:

• To identify novel ligands that modulate GPCR activity through unique mechanisms.
• To explore the stabilization of GPCR-G protein-β-arrestin complexes for sustained signaling.
• To discover compounds with broad applicability across different GPCRs.

Main Methods:

• Development and application of the survival pressure selection (SPS) method, a high-throughput platform for GPCR agonist discovery.
• Identification of an allosteric ligand stabilizing a GPCR-G protein-β-arrestin megacomplex.
• Testing the compound's pan-receptor activation across Family A GPCRs, including GPR119, β1AR, and β2AR.

Main Results:

• An allosteric ligand, identified as atazanavir, was found to stabilize a GPCR-G protein-β-arrestin megacomplex.
• This stabilization leads to sustained receptor signaling after receptor internalization.
• Atazanavir demonstrated pan-receptor activation across multiple Family A GPCRs, including GPR119, β1AR, and β2AR.

Conclusions:

• A novel mechanism of GPCR regulation involving the stabilization of a GPCR-G protein-β-arrestin megacomplex has been uncovered.
• This mechanism allows for sustained GPCR signaling and offers broad applicability across various GPCRs.
• The findings open new therapeutic avenues for developing drugs targeting GPCRs.