A biased allosteric modulator is a molecular glue for β2AR dimerization.

Abstract

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.