Spatiotemporal complexity and druggability of PTH1R: insights from small molecules and peptides

The parathyroid hormone type 1 receptor (PTH1R) is a class B GPCR that plays a vital role in calcium and phosphate homeostasis, bone turnover, and skeletal growth. It serves as a paradigmatic model for studying the spatial and temporal aspects of GPCR signaling, especially the prolonged cAMP signaling from endosomes and ligand-dependent location-biased agonism. Here, we review how small molecules and engineered peptides are advancing both the mechanistic understanding of this complex signaling process and its physiological significance, as well as drug discovery at PTH1R. Key developments include the orally administered small Gs-biased agonist PCO371, which binds the intracellular transmembrane region of the receptor; the negative non-peptidic allosteric modulator Pitt12, which decreases PTH-induced cAMP from an extracellular vestibule; backbone-modified, conformationally selective peptides, which have dissected and advanced our understanding of the mechanism and biological relevance of endosomal cAMP signaling. Together, these tools are clarifying the structural basis of signaling bias and PTH1R’s druggability, thereby enabling the development of therapies for bone and mineral diseases. • PTH1R regulates calcium, phosphate, and bone and is a key drug target • Small molecules reveal distinct binding sites and biased signaling • Endosomal cAMP signals drive unique, location-specific endocrine responses • Engineered peptides fine-tune PTH1R signaling duration and pathway