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

The parathyroid hormone type 1 receptor (PTH1R) is a prototypical class B1 G-protein-coupled receptor that couples to both G(q) and G(s), having a crucial role in calcium homeostasis and serving as a therapeutic target for osteoporosis. Therapies targeting PTH1R face challenges because of G(q)-associated prolonged signaling, which leads to bone resorption. To address this, selective activation of G(s) signaling is desirable. However, the structural basis of G(q)-mediated signaling remains unclear, limiting the development of signal-selective drugs. Here, we present cryo-electron microscopy structures of the PTH1R-G(q) complex in two distinct extracellular conformations, demonstrating the role of N-linked glycans at N176(1.28) in stabilizing the ligand-tilted conformation. Comparison with a G(s)-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(q) signaling. These structural insights provide a foundation for understanding the molecular mechanisms of PTH1R signaling.