Scott Research

G protein-coupled receptors (GPCRs) are both the largest family of receptors and the largest family of drug targets encoded in the human genome. They are nature’s favorite receptors because they coordinate complex physiological responses to environmental stimuli through activation of one (or many) G protein signaling pathways, and through recruitment of G protein-coupled receptor kinases (GRKs) and arrestins that block further G protein signaling, promote receptor endocytosis and recycling and stimulate distinct intracellular signaling pathways.

Although widely used in medicine, drugs that target GPCRs have a Goldilocks problem: agonists activate too many pathways (i.e., some therapeutically useful pathways but many pathways that cause side effects) while antagonists inhibit too many (i.e., blocking pathways that cause disease but also blocking important normal pathways). Biasing GPCR signaling to focus activation or inhibition on therapeutically relevant pathways has been a holy grail in GPCR pharmacology for decades, and many labs (including our own) have discovered and characterized GPCR ligands that bias signaling, but progress towards biased drugs has been hampered by poor understanding of the mechanism(s) governing GPCR signaling bias.

Recently, we discovered a negative allosteric modulator of GRK and arrestin recruitment to the beta-2-adrenergic receptor (ß2AR). The structure of this molecule bound to the ß2AR revealed the first clear paradigm for evoking G protein signaling bias. We are now testing this paradigm and using it to design the next generation of safer and more effective GPCR-targeted drugs.