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

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月26日

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  • Fumiya K. Sano,
  • Kota Shimizume,
  • Kazuhiro Kobayashi,
  • Toshikuni Awazu,
  • Kouki Kawakami,
  • Hiroaki Akasaka,
  • Takaaki A. Kobayashi,
  • Tatsuki Tanaka,
  • Hiroyuki H. Okamoto,
  • Hisato Hirano,
  • Tsukasa Kusakizako,
  • Wataru Shihoya,
  • Yoshiaki Kise,
  • Yuzuru Itoh,
  • Ryuichiro Ishitani,
  • Yasushi Okada,
  • Yasushi Sako,
  • Masataka Yanagawa,
  • Asuka Inoue,
  • Osamu Nureki

摘要

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.