A biased allosteric modulator functions as a molecular glue to induce β ₂ AR dimerization

Family A G-protein coupled receptors (GPCRs) are typically described as monomers, yet growing evidence suggests they can form dimers with distinct signaling properties ^1–3 . The mechanisms and therapeutic potential of such dimerization, however, remain poorly understood. Here, we show that AP-7-168, an optimized derivative of a β-arrestin-biased negative allosteric modulator of the β ₂ -adrenergic receptor (β ₂ AR) that sustains bronchorelaxation in cell and tissue models ⁴ , functions as a molecular glue to promote β ₂ AR homodimerization. Cryo-EM 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 induces β ₂ AR dimerization and drives enlarged nanocluster formation. Combined with extensive functional studies, our findings unveil a novel allosteric mechanism by which a small molecule biases β ₂ AR signaling through dimerization, highlighting ligand-induced dimerization as a strategy for GPCR modulation.