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

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

SUBMITTER: Zhai X 

PROVIDER: S-EPMC9586930 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature