Structural Perspectives on Biased Allostery of GPCR Signaling.

G protein-coupled receptors (GPCRs) are highly dynamic membrane receptors with numerous subtypes and complex signal transduction pathways. Precise regulation of GPCR signaling is closely related to disease treatment but presents significant challenges with classical orthosteric ligands. Allosteric modulators, a class of emerging drug candidates, can selectively bind to the allosteric sites located outside the conserved orthosteric pocket. In particular, biased allosteric modulators (BAMs) can stabilize specific conformations of GPCRs to harness signal transduction with high selectivity and specificity, offering a novel approach to modulate GPCR pharmacology and develop safer therapeutic agents. In recent years, significant progress has been made in the study of GPCR allosteric modulation due to advancements in structural biology. However, knowledge about GPCR-biased allostery is still in its infancy. In this chapter, we present the most recent breakthroughs in the discovery of BAM binding site in GPCRs and provide structural insights into biased allostery of GPCR signaling.