Molecular mechanisms of ligand recognition by parathyroid hormone 1 (PTH1) and PTH2 receptors

The mammalian parathyroid hormone (PTH) / PTH receptor family includes PTH1 and PTH2 receptors and three related ligands (PTH, PTH-related protein (PTHrP) and tuberoinfundibular peptide of 39 residues (TIP39)). Here we comparatively and systematically review the pharmacological properties of PTH receptors and ligands, structure of the ligands, and molecular mechanisms of receptor-ligand interaction. The PTH1 receptor is activated by PTH and PTHrP but not by TIP39. The PTH2 receptor is activated by TIP39 but not by PTHrP. PTH strongly activates the human PTH2 receptor but is a weak partial agonist for rat and zebrafish PTH2 receptors. Receptor-G-protein interaction increases the receptor binding selectivity of PTHrP and TIP39. Despite different primary structures, the secondary structures of PTH, PTHrP and TIP39 are quite similar. Each ligand contains an N-terminal and a C-terminal a-helix in secondary structure-inducing conditions. Receptor-bound ligand structure is less well-characterized. The orientation of receptor-ligand interaction is highly similar for PTH and PTHrP binding to the PTH1 receptor and TIP39 interaction with the PTH2 receptor. Ligands bind according to a 'two-site' mechanism, in which the C-terminal portion of the ligand binds the extracellular N-terminal domain of the receptor (N-interaction), and the N-terminal ligand portion binds to the juxtamembrane receptor domain (J-interaction), The N-interaction provides most of the PTH1-receptor binding energy for PTH and PTHrP but provides less energy for PTH2 receptor-TIP39 interaction. The J-interaction stimulates G-protein activation. For the PTH-PTH1 receptor interaction, the efficacy-generating component of the J-interaction is independent of the N-domain of the receptor and C-terminal portion of the ligand. This finding suggests that it might be possible to design low molecular-weight PTH1 receptor agonists, which could be bone anabolic agents and used for the treatment of osteoporosis.