It is now widely accepted that allosteric signaling is beyond signal transmission to, or conformational change triggered at, a distal point within a structure; it also affects different cellular pathways and functions depending on the specific allosteric modulators. A family of signaling molecules that has attracted wide attention in recent years is the Class B1 G protein-coupled receptors (GPCRs). In the classic view of GPCR signaling, cyclic adenosine monophosphate (cAMP) production is accepted to be uniquely associated with signaling events at the plasma membrane. However, a growing number of studies over the past decade, especially for the parathyroid hormone type 1 receptor (PTH1R), demonstrate that cAMP is also produced at the endosomes through a different pathway after receptor internalization. Recent advances in the structural and computational characterization of this family of allosteric receptors provide new insights into the mechanisms of their activation or inhibition, as well as determinants of differential allosteric signaling. We focus on PTH1R as a prototypical member of the family and present our current understanding of the role of selected ligands in acting as positive or negative allosteric modulators and eliciting signaling location biases in the cell.
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