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Molecular insights into the distinct signaling duration for the peptide-induced PTH1R activation

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  • Xiuwen Zhai

    (Jinling Clinical Medical College of Nanjing Medical University)

  • Chunyou Mao

    (Sir Run Run Shaw Hospital, Zhejiang University School of Medicine
    Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou)

  • Qingya Shen

    (Zhejiang University Medical Center)

  • Shaokun Zang

    (Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine)

  • Dan-Dan Shen

    (Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine)

  • Huibing Zhang

    (Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine)

  • Zhaohong Chen

    (Jinling Clinical Medical College of Nanjing Medical University)

  • Gang Wang

    (Jinling Clinical Medical College of Nanjing Medical University)

  • Changming Zhang

    (Jinling Clinical Medical College of Nanjing Medical University)

  • Yan Zhang

    (Sir Run Run Shaw Hospital, Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine
    Zhejiang University School of Medicine)

  • Zhihong Liu

    (Jinling Clinical Medical College of Nanjing Medical University
    Zhejiang University Medical Center)

Abstract

The parathyroid hormone type 1 receptor (PTH1R), a class B1 G protein-coupled receptor, plays critical roles in bone turnover and Ca2+ homeostasis. Teriparatide (PTH) and Abaloparatide (ABL) are terms as long-acting and short-acting peptide, respectively, regarding their marked duration distinctions of the downstream signaling. However, the mechanistic details remain obscure. Here, we report the cryo-electron microscopy structures of PTH– and ABL–bound PTH1R-Gs complexes, adapting similar overall conformations yet with notable differences in the receptor ECD regions and the peptide C-terminal portions. 3D variability analysis and site-directed mutagenesis studies uncovered that PTH–bound PTH1R–Gs complexes display less motions and are more tolerant of mutations in affecting the receptor signaling than ABL–bound complexes. Furthermore, we combined the structural analysis and signaling assays to delineate the molecular basis of the differential signaling durations induced by these peptides. Our study deepens the mechanistic understanding of ligand-mediated prolonged or transient signaling.

Suggested Citation

  • Xiuwen Zhai & Chunyou Mao & Qingya Shen & Shaokun Zang & Dan-Dan Shen & Huibing Zhang & Zhaohong Chen & Gang Wang & Changming Zhang & Yan Zhang & Zhihong Liu, 2022. "Molecular insights into the distinct signaling duration for the peptide-induced PTH1R activation," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34009-x
    DOI: 10.1038/s41467-022-34009-x
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    1. Christoph Klenk & Maria Scrivens & Anina Niederer & Shuying Shi & Loretta Mueller & Elaine Gersz & Maurice Zauderer & Ernest S. Smith & Ralf Strohner & Andreas Plückthun, 2023. "A Vaccinia-based system for directed evolution of GPCRs in mammalian cells," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Shivani Sachdev & Brendan A. Creemer & Thomas J. Gardella & Ross W. Cheloha, 2024. "Highly biased agonism for GPCR ligands via nanobody tethering," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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