9B5Y

Cryo-EM structure of the LAPTH-bound PTH1R in complex with Gq

Summary for 9B5Y

• Entry DOI: 10.2210/pdb9b5y/pdb
• EMDB information: 44229
• Descriptor: Parathyroid hormone/parathyroid hormone-related peptide receptor, Guanine nucleotide-binding protein G(q), Long-acting parathyroid hormone analog, ... (6 entities in total)
• Functional Keywords: gpcr, pth1r, membrane protein, signaling protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 6
• Total formula weight: 199028.23

Authors

Zhang, X.,Liu, H.,Zhang, C.,Vilardaga, J.-P. (deposition date: 2024-03-22, release date: 2025-03-19, Last modification date: 2025-06-04)

Primary citation

Zhang, X.,Lee, J.Y.,Pacheco, J.,Sutkeviciute, I.,Anitha, A.K.,Liu, H.,Singh, S.,Ventura, C.,Savransky, S.,Khatri, A.,Zhang, C.,Bahar, I.,Vilardaga, J.P.
Allosteric mechanism in the distinctive coupling of G q and G s to the parathyroid hormone type 1 receptor.
Proc.Natl.Acad.Sci.USA, 122:e2426178122-e2426178122, 2025

PubMed Abstract: The mechanism determining the preferential stimulation of one heterotrimeric G protein signaling pathway over another by a ligand remains undetermined. By reporting the cryogenic electron microscopy (cryo-EM) structure of the parathyroid hormone (PTH) type 1 receptor (PTH1R) complexed with Gq and comparing its allosteric dynamics with that of PTH1R in complex with G, we uncover a mechanism underlying such preferences. We show that an allosteric coupling between the ligand PTH and the C-terminal helix α5 of the Gα subunit controls the stability of the PTH1R complex with the specific G protein, G or G. Single-cell-level experiments further validate the G protein-selective effects of the PTH binding pose by demonstrating the differential, G protein-dependent residence times and affinity of this ligand at the PTH1R binding site. The findings deepen our understanding of the selective coupling of PTH1R to G or G and how it relates to the stability and kinetics of ligand binding. They explain the observed variability in the ligand-binding affinity of a GPCR when coupled to different G proteins.

PubMed: 40138341
DOI: 10.1073/pnas.2426178122

Experimental method

ELECTRON MICROSCOPY (3.49 Å)