A pan-positive allosteric modulator that mediates sustainable GPCR activation

Approximately 1/3 of all clinical drugs exert their therapeutic effects by modulating the activity of G protein-coupled receptors (GPCRs). Thus, there is a constant interest in finding novel ways to modulate GPCR activity. In this work, through a newly established Survival Pressure Selection (SPS) method for high-throughput screening of GPCR agonists, we discover that atazanavir functions as an agonist for GPR119. Further studies suggest that atazanavir is capable of activating a number of Family A GPCRs, including the β ₁ adrenergic receptor (β ₁ AR), the β ₂ adrenergic receptor (β ₂ AR) and the μ opoioid receptor (μOR). Cryo-EM structures reveal that atazanavir binds to an allosteric pocket near TM6/7 in both GPR119 and the β ₁ AR. Pharmacological studies suggest that atazanavir mediates non-canonical signaling of Family A GPCRs. During this process, G protein and β-arrestin are spatially close, but β-arrestin forms a complex with the receptor and G protein instead of desensitizing G protein signaling, thus resulting in sustained G protein signaling. The work expands the signal transduction modes and pharmacological properties of allosteric modulators for GPCRs and provides a general starting point for developing therapeutics targeting this allosteric site.