Projects per year
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.
- g protein-coupled receptor
- membrane protein
- 4 Active
ARC Industrial Transformation Training Centre for Cryo-Electron Microscopy of Membrane Proteins for Drug Discovery
Sexton, P., Rouiller, I., Wootten, D., van Oijen, A., Parker, M. W., Lucet, I., Griffin, M. D. W., Adams, D. J., Czabotar, P. E., Flocco, M., Han, S., Shepherd, R., Ciferri, C., Williams, P. A., Brown, D., Schreuder, H., Reedtz-Runge, S., Drinkwater, C., Howard, B. L., Betigeri, G. & Pryor, E.
23/03/21 → 22/03/26
1/01/19 → 31/12/23
Slava Kitaeff (Manager) & David Powell (Manager)Office of the Vice-Provost (Research and Research Infrastructure)
Georg Ramm (Manager), Simon Andrew Crawford (Operator), Hariprasad Venugopal (Operator), Joan Marea Clark (Operator) & Gediminas Gervinskas (Operator)Faculty of Medicine Nursing and Health Sciences Research Platforms