A biased allosteric modulator functions as a molecular glue to induce β2AR dimerization. bioRxiv 2025 Oct 22
Date
11/24/2025Pubmed ID
41279134Pubmed Central ID
PMC12633310DOI
10.1101/2025.10.21.683802Abstract
Family A G-protein coupled receptors (GPCRs) are typically described as monomers, yet growing evidence suggests they can form dimers with distinct signaling properties1-3. 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 β2-adrenergic receptor (β2AR) that sustains bronchorelaxation in cell and tissue models4, functions as a molecular glue to promote β2AR 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 β2AR dimerization and drives enlarged nanocluster formation. Combined with extensive functional studies, our findings unveil a novel allosteric mechanism by which a small molecule biases β2AR signaling through dimerization, highlighting ligand-induced dimerization as a strategy for GPCR modulation.
Author List
Shen J, Peddada TN, Komolov KE, De Pascali F, Garces AM, Wang H, Lerch MT, Benovic JL, Xu J, Kobilka BKAuthors
Alexander M. Garces Postdoctoral Researcher 1 in the Biophysics department at Medical College of WisconsinMichael Lerch PhD Associate Professor in the Biophysics department at Medical College of Wisconsin
