Nanfang University of Science and Technology Team Identifies How GPCR Dimerization Reprograms Signaling

A new mechanism by which a small-molecule compound acts like “molecular glue,” bringing G protein-coupled receptors (GPCRs) together to reprogram signaling, has been reported in Nature, one of the world’s leading scientific journals.

According to the international journal Nature on the 28th, a research team led by Associate Professor Xu Jun of the School of Medicine at Nanfang University of Science and Technology and a team led by Stanford University Professor Brian Kobilka found that the small-molecule modulator AP stabilizes receptor dimers and alters signaling selectivity at the β₂-adrenergic receptor (β₂AR), a key target for treating asthma and chronic obstructive pulmonary disease.

The study goes beyond the conventional pharmacological framework in which GPCRs function only as individual monomers, showing that drugs can control the receptors’ higher-order assembly states. GPCRs are the largest family of membrane receptors in the human body and are involved in neural, cardiovascular, metabolic and immune functions. About one-third of marketed drugs act on these receptors directly or indirectly.

Using β₂AR as a model, the researchers confirmed that AP does not simply bind to an individual receptor and change its structure; instead, it induces two β₂AR molecules to form a stable dimer. Structural studies showed that AP binds to the interface between the two β₂ARs, with two AP molecules each fitting into an interface pocket formed by the two receptors and locking them into a specific dimer structure.

This is a different mode of action from that of conventional orthosteric ligands. Rather than merely binding to a receptor, a drug can stabilize interactions between receptors and directly control the higher-order assembly state of GPCRs.

Functional studies also revealed the significance of dimer formation. The AP-induced β₂AR dimer continued to bind effectively to Gs proteins and maintain downstream signaling, while recruitment of β-arrestin was markedly inhibited. The researchers said the receptor interface and structural environment created by dimer formation altered the conditions for binding of β-arrestin and related GRK proteins, reducing receptor desensitization and internalization while sustaining Gs-cAMP signaling that promotes airway relaxation.

In simple terms, AP does not merely “turn” β₂AR on or off; it changes how the receptor selects among different signaling pathways. It preserves beneficial G protein signaling while reducing negative regulation mediated by β-arrestin, producing a more sustained signaling output. This also provides a structural and molecular explanation for the sustained bronchodilatory effects AP had previously demonstrated.

The researchers further confirmed that AP-stabilized β₂AR dimers are not isolated and can form higher-order receptor assemblies. This suggests that GPCR dimerization and oligomerization may be important biological mechanisms for organizing and regulating cellular signaling, rather than merely structural phenomena.

On this basis, the researchers proposed a new model for GPCR drug modulation: “small-molecule ligand → stabilization of receptor dimers and oligomers → remodeling of receptor structure and spatial organization → changes in signaling protein selectivity → regulation of physiological function.” This extends the classical pharmacological framework of “ligand-monomeric receptor-signaling protein” by incorporating the higher-order assembly states of GPCRs into drug design.

The study also offers a new strategy for developing drugs for respiratory diseases. β₂AR is one of the most important drug targets for treating asthma and other obstructive airway diseases. Rather than changing only the degree of receptor activation, regulating receptor dimerization could precisely “reprogram” different signaling pathways in a way that preserves bronchodilation while reducing receptor desensitization, the researchers said.

The researchers said the strategy not only provides a new theoretical framework for β₂AR pharmacology but also could make “regulation of receptor dimerization” a broadly applicable strategy for GPCR drug development. Designing small molecules that selectively stabilize specific receptor dimers or oligomeric structures could extend the approach to other GPCR targets and support drug development for asthma and chronic obstructive pulmonary disease, as well as neurological, cardiovascular and metabolic diseases.

To identify the mechanism, the researchers combined cryo-electron microscopy structural analysis, single-molecule Förster resonance energy transfer (smFRET), bioluminescence resonance energy transfer (BRET), and biochemical and biophysical experiments to comprehensively analyze how AP works at the structural, dynamic and functional levels.

Previously, Xu Jun’s team reported in Nature Communications that a negative modulator of the orphan receptor GPR3 stabilizes the receptor’s dimeric state and inhibits downstream signaling. However, it remained unclear whether this mechanism is widespread among class A GPCRs and what its potential for clinical application might be. The new Nature paper offers a fresh answer to these questions.

Associate Professor Xu Jun and Stanford University Professor Brian Kobilka, a Nobel Prize winner in chemistry, served as co-corresponding authors. Stanford postdoctoral researchers Jieming Shen and Teja Nikhil Peddada were co-first authors.

Associate Professor Xu Jun has long focused on the molecular mechanisms of GPCR signaling, receptor dynamics and higher-order assembly, ligand discovery, and early-stage drug development. The findings highlight the School of Medicine at Nanfang University of Science and Technology’s research strengths in GPCR receptor signaling regulation and drug development. They also demonstrate how collaboration between institutions can help address major life sciences questions and translate basic research into disease treatment.