Insights into G-protein coupling preference from cryo-EM structures of G-bound PTH1R.

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.