8FLT

Human PTH1R in complex with M-PTH(1-14) and Gs

Summary for 8FLT

• Entry DOI: 10.2210/pdb8flt/pdb
• EMDB information: 29283 29284 29285 29286 29287
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: gpcr, agonist, hormone, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 174596.89

Authors

Cary, B.P.,Belousoff, M.J.,Piper, S.J.,Wootten, D.,Sexton, P.M. (deposition date: 2022-12-22, release date: 2023-04-26, Last modification date: 2023-06-14)

Primary citation

Cary, B.P.,Gerrard, E.J.,Belousoff, M.J.,Fletcher, M.M.,Jiang, Y.,Russell, I.C.,Piper, S.J.,Wootten, D.,Sexton, P.M.
Molecular insights into peptide agonist engagement with the PTH receptor.
Structure, 31:668-676.e5, 2023

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 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.

PubMed: 37148874
DOI: 10.1016/j.str.2023.04.002

Experimental method

ELECTRON MICROSCOPY (3.03 Å)