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Molecular insights into the distinct signaling duration for the peptide-induced PTH1R activation.
Zhai, Xiuwen; Mao, Chunyou; Shen, Qingya; Zang, Shaokun; Shen, Dan-Dan; Zhang, Huibing; Chen, Zhaohong; Wang, Gang; Zhang, Changming; Zhang, Yan; Liu, Zhihong.
Afiliação
  • Zhai X; National Clinical Research Center of Kidney Diseases, Jinling Clinical Medical College of Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
  • Mao C; Center for Structural Pharmacology and Therapeutics Development, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. maochunyou@zju.edu.cn.
  • Shen Q; Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. maochunyou@zju.edu.cn.
  • Zang S; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China.
  • Shen DD; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • Zhang H; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • Chen Z; Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • Wang G; National Clinical Research Center of Kidney Diseases, Jinling Clinical Medical College of Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
  • Zhang C; National Clinical Research Center of Kidney Diseases, Jinling Clinical Medical College of Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
  • Zhang Y; National Clinical Research Center of Kidney Diseases, Jinling Clinical Medical College of Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
  • Liu Z; Center for Structural Pharmacology and Therapeutics Development, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. zhang_yan@zju.edu.cn.
Nat Commun ; 13(1): 6276, 2022 10 21.
Article em En | MEDLINE | ID: mdl-36271004
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Teriparatida / Receptor Tipo 1 de Hormônio Paratireóideo Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Teriparatida / Receptor Tipo 1 de Hormônio Paratireóideo Idioma: En Ano de publicação: 2022 Tipo de documento: Article