Nucleic acid ligands act as a PAM and agonist depending on the intrinsic ligand binding state of P2RY2

Significance Discovery of ligands for G protein–coupled receptors (GPCRs) is of importance in receptor biology and pharmacology but is still a challenging issue. Here, we propose a method for the discovery of ligands against GPCRs by employing a virus-like particle (VLP) and show unique properties of identified nucleic acid aptamers for GPCR. One aptamer raised against purinergic receptor P2Y2 (P2RY2), a GPCR, behaves like a partial agonist to unliganded receptor, whereas it exhibits a positive allosteric modulator (PAM) activity to liganded receptor. We demonstrate the validity of our aptamer screening method targeting VLP-stabilized GPCR and a unique aptamer with dual function, agonist and PAM, for GPCR, depending on whether the intrinsic ligand is prebound to the receptor.