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

IF 13.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Nature chemical biology Pub Date : 2025-06-26 DOI:10.1038/s41589-025-01957-6

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

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Abstract

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.

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从gq结合PTH1R的低温电镜结构观察g蛋白偶联偏好

甲状旁腺激素1型受体（PTH1R）是一种典型的B1类g蛋白偶联受体，可与Gq和Gs偶联，在钙稳态中起重要作用，是骨质疏松症的治疗靶点。针对PTH1R的治疗面临挑战，因为gq相关的延长信号传导导致骨吸收。为了解决这个问题，需要选择性地激活Gs信号。然而，gq介导的信号传导的结构基础尚不清楚，限制了信号选择性药物的发展。在这里，我们展示了两种不同细胞外构象的PTH1R-Gq复合物的低温电镜结构，证明了N1761.28位点的n -链聚糖在稳定配体倾斜构象中的作用。与gs结合的PTH1R结构的比较突出了涉及Gα C端和受体胞内环2的关键相互作用在Gq信号传导中的作用。这些结构见解为理解PTH1R信号传导的分子机制提供了基础。

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来源期刊

Nature chemical biology 生物-生化与分子生物学

CiteScore

23.90

自引率

1.40%

发文量

238

审稿时长

12 months

期刊介绍： Nature Chemical Biology stands as an esteemed international monthly journal, offering a prominent platform for the chemical biology community to showcase top-tier original research and commentary. Operating at the crossroads of chemistry, biology, and related disciplines, chemical biology utilizes scientific ideas and approaches to comprehend and manipulate biological systems with molecular precision. The journal embraces contributions from the growing community of chemical biologists, encompassing insights from chemists applying principles and tools to biological inquiries and biologists striving to comprehend and control molecular-level biological processes. We prioritize studies unveiling significant conceptual or practical advancements in areas where chemistry and biology intersect, emphasizing basic research, especially those reporting novel chemical or biological tools and offering profound molecular-level insights into underlying biological mechanisms. Nature Chemical Biology also welcomes manuscripts describing applied molecular studies at the chemistry-biology interface due to the broad utility of chemical biology approaches in manipulating or engineering biological systems. Irrespective of scientific focus, we actively seek submissions that creatively blend chemistry and biology, particularly those providing substantial conceptual or methodological breakthroughs with the potential to open innovative research avenues. The journal maintains a robust and impartial review process, emphasizing thorough chemical and biological characterization.