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Structure paper

TitleMolecular insights into peptide agonist engagement with the PTH receptor.
Journal, issue, pagesStructure, Vol. 31, Issue 6, Page 668-676.e5, Year 2023
Publish dateJun 1, 2023
AuthorsBrian 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 AbstractThe 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 linksStructure / PubMed:37148874
MethodsEM (single particle)
Resolution2.55 - 3.09 Å
Structure data

29283

8flq

EMDB-29283, PDB-8flq:
Human PTH1R in complex with PTH(1-34) and Gs
Method: EM (single particle) / Resolution: 2.55 Å

29284

8flr

EMDB-29284, PDB-8flr:
Human PTH1R in complex with PTHrP and Gs
Method: EM (single particle) / Resolution: 2.94 Å

29285

8fls

EMDB-29285, PDB-8fls:
Human PTH1R in complex with Abaloparatide and Gs
Method: EM (single particle) / Resolution: 3.09 Å

29286

8flt

EMDB-29286, PDB-8flt:
Human PTH1R in complex with M-PTH(1-14) and Gs
Method: EM (single particle) / Resolution: 3.03 Å

29287

8flu

EMDB-29287, PDB-8flu:
Human PTH1R in complex with LA-PTH and Gs
Method: EM (single particle) / Resolution: 2.76 Å

Chemicals

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)
  • lama glama (llama)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN / GPCR / agonist / hormone

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