A biased allosteric modulator is a molecular glue for β2AR dimerization

Family A G-protein-coupled receptors (GPCRs) are typically described as monomers, yet growing evidence suggests that they can form dimers with distinct signalling properties1–3. However, the mechanisms and therapeutic potential of such dimerization remain poorly understood. Here we show that AP-7-168, an optimized derivative of a β-arrestin-biased negative allosteric modulator of the β2-adrenergic receptor (β2AR) that sustains bronchorelaxation in cell and tissue models4, functions as a molecular glue to stabilize β2AR homodimerization. Cryogenic electron microscopy structures reveal a unique binding mode in which two AP-7-168 molecules pack within a pocket formed by transmembrane helices 3, 4 and 5 of two protomers, stabilizing a dimeric conformation that selectively prevents β-arrestin coupling. In cells, AP-7-168 robustly stabilizes β2AR dimerization and drives enlarged nanocluster formation. Combined with extensive functional studies, our findings identify an allosteric mechanism by which a small molecule biases β2AR signalling through dimerization, highlighting ligand-stabilized dimerization as a strategy for GPCR modulation. AP-7-168, an optimized derivative of a β-arrestin-biased negative allosteric modulator of the β2-adrenergic receptor (β2AR), functions as a molecular glue to stabilize β2AR homodimerization.