Molecular insights into peptide agonist engagement with the PTH receptor

The parathyroid hormone (PTH) 1 receptor (PTH1R) is a G protein-coupled receptor (GPCR) that regulates skeletal development and calcium homeostasis. Here, we describe cryo-EM structures of the PTH1R in com-plex with fragments of the two hormones, PTH and PTH-related protein, the drug abaloparatide, as well as the engineered tool compounds, long-acting PTH (LA-PTH) and the truncated peptide, M-PTH(1-14). We found that the critical N terminus of each agonist engages the transmembrane bundle in a topologically similar fashion, reflecting similarities in measures of Gas activation. The full-length peptides induce subtly different extracellular domain (ECD) orientations relative to the transmembrane domain. In the structure bound to M-PTH, the ECD is unresolved, demonstrating that the ECD is highly dynamic when unconstrained by a pep-tide. High resolutions enabled identification of water molecules near peptide and G protein binding sites. Our results illuminate the action of orthosteric agonists of the PTH1R.

Automated summary

This study describes the cryo-EM structures of PTH1R in complex with different agonists, such as PTH, PTH-related protein, abaloparatide, long-acting PTH, and truncated peptide M-PTH(1-14). The N terminus of each agonist engages the transmembrane bundle in a similar way, leading to Gas activation. The full-length peptides induce subtle differences in the orientation of the extracellular domain, while in the structure bound to M-PTH, the extracellular domain remains unresolved, indicating its high dynamic nature in the absence of peptides. Water molecules near peptide and G protein binding sites were also identified. These results provide insights into the mechanism of action of orthosteric agonists of PTH1R.