{"title":"从gq结合PTH1R的低温电镜结构观察g蛋白偶联偏好","authors":"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","doi":"10.1038/s41589-025-01957-6","DOIUrl":null,"url":null,"abstract":"<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><figure></figure>","PeriodicalId":18832,"journal":{"name":"Nature chemical biology","volume":"58 1","pages":""},"PeriodicalIF":13.7000,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Insights into G-protein coupling preference from cryo-EM structures of Gq-bound PTH1R\",\"authors\":\"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\",\"doi\":\"10.1038/s41589-025-01957-6\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<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><figure></figure>\",\"PeriodicalId\":18832,\"journal\":{\"name\":\"Nature chemical biology\",\"volume\":\"58 1\",\"pages\":\"\"},\"PeriodicalIF\":13.7000,\"publicationDate\":\"2025-06-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature chemical biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1038/s41589-025-01957-6\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature chemical biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41589-025-01957-6","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Insights into G-protein coupling preference from cryo-EM structures of Gq-bound PTH1R
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.
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