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

doi:10.1016/j.str.2023.04.002

Molecular insights into peptide agonist engagement with the PTH receptor

Structure. 2023 Jun 1;31(6):668-676.e5. doi: 10.1016/j.str.2023.04.002. Epub 2023 May 5.

Authors

Brian P Cary¹, Elliot J Gerrard², Matthew J Belousoff³, Madeleine M Fletcher², Yan Jiang³, Isabella C Russell³, Sarah J Piper³, Denise Wootten⁴, Patrick M Sexton⁵

Affiliations

¹ Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, VIC, Australia; ARC Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, VIC, Australia. Electronic address: brian.cary@monash.edu.
² Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, VIC, Australia.
³ Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, VIC, Australia; ARC Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, VIC, Australia.
⁴ Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, VIC, Australia; ARC Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, VIC, Australia. Electronic address: denise.wootten@monash.edu.
⁵ Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, VIC, Australia; ARC Centre for Cryo-Electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, VIC, Australia. Electronic address: patrick.sexton@monash.edu.

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

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.

Keywords: Cryo-EM; GPCR; PTH; g protein-coupled receptor; hormone; membrane protein; parathyroid; peptides.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

GTP-Binding Proteins / metabolism
Parathyroid Hormone* / chemistry
Parathyroid Hormone* / metabolism
Parathyroid Hormone* / pharmacology
Peptides / metabolism
Peptides / pharmacology
Receptor, Parathyroid Hormone, Type 1* / chemistry
Receptor, Parathyroid Hormone, Type 1* / metabolism
Receptors, G-Protein-Coupled / metabolism

Substances

Receptor, Parathyroid Hormone, Type 1
Parathyroid Hormone
Peptides
Receptors, G-Protein-Coupled
GTP-Binding Proteins