Molecular insights into peptide agonist engagement with the PTH receptor

Brian P. Cary, Elliot J. Gerrard, Matthew J. Belousoff, Madeleine M. Fletcher, Yan Jiang, Isabella C. Russell, Sarah J. Piper, Denise Wootten, Patrick M. Sexton

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)


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 complex 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 Gαs 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 peptide. 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.

Original languageEnglish
Pages (from-to)668-676.e5
Number of pages14
Issue number6
Publication statusPublished - 1 Jun 2023


  • Cryo-EM
  • g protein-coupled receptor
  • GPCR
  • hormone
  • membrane protein
  • parathyroid
  • peptides
  • PTH

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