9JR3

Cryo-EM structure of PTH-PTH1R-Gq (tilted state)

Summary for 9JR3

• Entry DOI: 10.2210/pdb9jr3/pdb
• EMDB information: 61747
• Descriptor: Parathyroid hormone/parathyroid hormone-related peptide receptor, Parathyroid hormone, Guanine nucleotide-binding protein G(i) subunit alpha-1 (miniGq), ... (8 entities in total)
• Functional Keywords: class b gpcrs, gq, pth, signaling protein, signaling protein-immune system complex, signaling protein/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 169415.80

Authors

Sano, F.K.,Hirano, H.,Itoh, Y.,Nureki, O. (deposition date: 2024-09-29, release date: 2024-10-16, Last modification date: 2025-07-09)

Primary citation

Sano, F.K.,Shimizume, K.,Kobayashi, K.,Awazu, T.,Kawakami, K.,Akasaka, H.,Kobayashi, T.A.,Tanaka, T.,Okamoto, H.H.,Hirano, H.,Kusakizako, T.,Shihoya, W.,Kise, Y.,Itoh, Y.,Ishitani, R.,Okada, Y.,Sako, Y.,Yanagawa, M.,Inoue, A.,Nureki, O.
Insights into G-protein coupling preference from cryo-EM structures of G q -bound PTH1R.
Nat.Chem.Biol., 2025

PubMed Abstract: The parathyroid hormone type 1 receptor (PTH1R) is a prototypical class B1 G-protein-coupled receptor that couples to both G and G, having a crucial role in calcium homeostasis and serving as a therapeutic target for osteoporosis. Therapies targeting PTH1R face challenges because of G-associated prolonged signaling, which leads to bone resorption. To address this, selective activation of G signaling is desirable. However, the structural basis of G-mediated signaling remains unclear, limiting the development of signal-selective drugs. Here, we present cryo-electron microscopy structures of the PTH1R-G complex in two distinct extracellular conformations, demonstrating the role of N-linked glycans at N176 in stabilizing the ligand-tilted conformation. Comparison with a G-bound PTH1R structure highlights the role of key interactions involving both the C terminus of Gα and the receptor's intracellular loop 2 in G signaling. These structural insights provide a foundation for understanding the molecular mechanisms of PTH1R signaling.

PubMed: 40571720
DOI: 10.1038/s41589-025-01957-6

Experimental method

ELECTRON MICROSCOPY (2.8 Å)