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Title | Molecular insights into peptide agonist engagement with the PTH receptor. |
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Journal, issue, pages | Structure, Vol. 31, Issue 6, Page 668-676.e5, Year 2023 |
Publish date | Jun 1, 2023 |
Authors | 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 / |
PubMed Abstract | 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 ...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. |
External links | Structure / PubMed:37148874 |
Methods | EM (single particle) |
Resolution | 2.55 - 3.09 Å |
Structure data | EMDB-29283, PDB-8flq: EMDB-29284, PDB-8flr: EMDB-29285, PDB-8fls: EMDB-29286, PDB-8flt: EMDB-29287, PDB-8flu: |
Chemicals | ChemComp-HOH: |
Source |
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Keywords | MEMBRANE PROTEIN / GPCR / agonist / hormone |