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

Xiuwen Zhai, Chunyou Mao (), Qingya Shen, Shaokun Zang, Dan-Dan Shen, Huibing Zhang, Zhaohong Chen, Gang Wang, Changming Zhang, Yan Zhang () and Zhihong Liu ()
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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
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
Zhihong Liu: Jinling Clinical Medical College of Nanjing Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34009-x

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