Insights into G-protein coupling preference from cryo-EM structures of Gq-bound PTH1R
Fumiya K. Sano, Kota Shimizume, Kazuhiro Kobayashi, Toshikuni Awazu, Kouki Kawakami, Hiroaki Akasaka, Takaaki A. Kobayashi, Tatsuki Tanaka, Hiroyuki Okamoto, Hisato Hirano, Tsukasa Kusakizako, Wataru Shihoya, Yoshiaki Kise, Yuzuru Itoh, Ryuichiro Ishitani, Yasushi Okada, Yasushi Sako, Masataka Yanagawa, Asuka Inoue, Osamu Nureki
Abstract
The parathyroid hormone type 1 receptor (PTH1R) is a prototypical class B1 G-protein-coupled receptor that couples to both Gq and Gs, having a crucial role in calcium homeostasis and serving as a therapeutic target for osteoporosis. Therapies targeting PTH1R face challenges because of Gq-associated prolonged signaling, which leads to bone resorption. To address this, selective activation of Gs signaling is desirable. However, the structural basis of Gq-mediated signaling remains unclear, limiting the development of signal-selective drugs. Here, we present cryo-electron microscopy structures of the PTH1R–Gq complex in two distinct extracellular conformations, demonstrating the role of N-linked glycans at N1761.28 in stabilizing the ligand-tilted conformation. Comparison with a Gs-bound PTH1R structure highlights the role of key interactions involving both the C terminus of Gα and the receptor’s intracellular loop 2 in Gq signaling. These structural insights provide a foundation for understanding the molecular mechanisms of PTH1R signaling. Description of the cryo-EM structures of the parathyroid hormone type 1 receptor associated with Gq reveals two distinct extracellular conformations with N-glycans stabilizing a ligand-tilted conformation.