2026年8月19日，南方科技大学医学院徐俊等合作在《自然》上发表研究，发现一种β2AR的偏向性负向变构调节剂衍生物AP-7-168可作为分子胶稳定β2AR同源二聚化，通过二聚化机制偏向性调控β2AR信号传导。

A家族G蛋白偶联受体（GPCR）通常被描述为单体，但越来越多的证据表明它们可以形成具有不同信号传导特性的二聚体。然而，这种二聚化的机制和治疗潜力仍知之甚少。本研究发现，AP-7-168——一种β-arrestin偏向性β2-肾上腺素能受体（β2AR）负向变构调节剂的优化衍生物，该衍生物在细胞和组织模型中可持续维持支气管舒张——可作为分子胶稳定β2AR同源二聚化。冷冻电镜结构揭示了一种独特的结合模式，其中两个AP-7-168分子堆积在两个原聚体的跨膜螺旋3、4和5所形成的口袋内，稳定了一种选择性阻止β-arrestin偶联的二聚体构象。在细胞中，AP-7-168可强力稳定β2AR二聚化并驱动扩大的纳米簇形成。结合广泛的功能研究，研究人员的发现阐明了一种变构机制，即小分子通过二聚化偏向性调控β2AR信号传导，突显了配体稳定的二聚化可作为GPCR调节的一种策略。

附：英文原文

Title: A biased allosteric modulator is a molecular glue for β2AR dimerization

Author: Shen, Jiemin, Peddada, Teja Nikhil, Komolov, Konstantin E., De Pascali, Francesco, Garces, Alexander M., Wang, Haoqing, Ehsan, Muhammad, Chae, Pil Seok, Lerch, Michael T., Benovic, Jeffrey L., Xu, Jun, Kobilka, Brian K.

Issue&Volume: 2026-08-19

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 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.

DOI: 10.1038/s41586-026-10892-y

Source: https://www.nature.com/articles/s41586-026-10892-y