9Q3L

CryoEM structure of beta2-adrenergic receptor dimer mediated by a biased allosteric modulator in lipid nanodisc

This is a non-PDB format compatible entry.

Summary for 9Q3L

• Entry DOI: 10.2210/pdb9q3l/pdb
• EMDB information: 72202
• Descriptor: Beta-2 adrenergic receptor, TETRADECANE, EICOSANE, ... (5 entities in total)
• Functional Keywords: gpcr, adrenergic receptor, dimer, molecular glue, biased allosteric modulator, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 106103.82

Authors

Shen, J.,Kobilka, B.K. (deposition date: 2025-08-18, release date: 2026-08-19, Last modification date: 2026-09-02)

Primary citation

Shen, J.,Peddada, T.N.,Komolov, K.E.,De Pascali, F.,Garces, A.M.,Wang, H.,Ehsan, M.,Chae, P.S.,Lerch, M.T.,Benovic, J.L.,Xu, J.,Kobilka, B.K.
A biased allosteric modulator is a molecular glue for beta 2 AR dimerization.
Nature, 2026

PubMed 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 properties. 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 β-adrenergic receptor (βAR) that sustains bronchorelaxation in cell and tissue models, functions as a molecular glue to stabilize βAR 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 βAR dimerization and drives enlarged nanocluster formation. Combined with extensive functional studies, our findings identify an allosteric mechanism by which a small molecule biases βAR signalling through dimerization, highlighting ligand-stabilized dimerization as a strategy for GPCR modulation.

PubMed: 42618785
DOI: 10.1038/s41586-026-10892-y

Experimental method

ELECTRON MICROSCOPY (2.5 Å)