Laboratory of Signal Transduction Reveals Molecular Mechanism for Functional Selectivity of GPCR

In a recent study, Professor Rui-Ping Xiao and her research group at Institute of Molecular Medicine of Peking University has provided an essential experimental evidence to support the new paradigm of functional selectivity for G protein-coupled receptor (GPCR) signal transduction. The study was published online on May 15 in The Journal of Biological Chemistry (

The GPCR superfamily, a class of membrane proteins responsible for transmembrane signal transduction, has been a focal point in the field of biomedical research as well as drug discovery and development. Drugs targeting this superfamily account for about 50% of all prescription pharmaceuticals on the market. Recently, a paradigm called functional selectivity of GPCR signaling has been proposed to explain how different ligands can cause a single GPCR to relay diverse downstream signals. According to this paradigm, ligand-specific receptor signaling (biased signaling) depends on ligand-specific receptor conformation. However, this hypothesis suffers from the lack of structure-function-based experimental evidence.

As early as 2003, Rui-Ping Xiao and her team discovered that while most β2-adrenergic receptor (β2-AR) agonists stimulate the receptor to activate both the stimulatory G proteins (Gs) and the inhibitory G proteins (Gi) to produce dual signaling, fenoterol stimulates the Gs-selective β2-ARsignaling. However, the molecular mechanism for the functional selectivity of β2-AR signaling remains elusive.

The latest study by Woo et al. demonstrated that “tyrosine 308 is necessary for Gs-biased signaling of β2-AR”. The researchers found that (R,R’)-4'-aminofenoterol, an analog of fenoterol, stimulates the wild-type β2-AR to produce selectively Gs signaling but stimulates the β2-AR Y308F mutant to produce Gs and Gi dual signaling. Further application of a cohort of fenoterol derivatives in computer modeling studies and biological assays on cardiomyocytes led to the identification of a hydrogen bond interaction between the 4’-O or 4’-N of the ligand and the phenyl hydroxyl group of β2-AR-Y308 necessary for Gs-biased signaling (Figure).

The study reported for the first time the identification of a ligand-receptor interaction dedicated to functional selectivity. It also revealed the structural basis of functional selectivity for β2-AR signaling and provided structural insights for structure-based design of signaling pathway-specific drugs.

National Institute on Aging of the United States National Institutes of Health (NIH), Medical University of Lublin in Poland, Torrey Pines Institute for Molecular Studies and SRI International participated in this study. The study was funded by the ‘973’ project of Ministry of Science and Technology of China, National Science Foundation of China, Beijing Key Laboratory of Cardiometabolic Molecular Medicine Peking University, Intramural Research Program of the United States National Institutes of Health National Institute on Aging, and the Foundation of Polish Science.