Allosteric mechanism in the distinctive coupling of G_q and G_s to the parathyroid hormone type 1 receptor.

ABSTRACT: The mechanism determining the preferential stimulation of one heterotrimeric G protein signaling pathway over another by a ligand remains undetermined. By reporting the cryogenic electron microscopy (cryo-EM) structure of the parathyroid hormone (PTH) type 1 receptor (PTH1R) complexed with Gq and comparing its allosteric dynamics with that of PTH1R in complex with G_s, we uncover a mechanism underlying such preferences. We show that an allosteric coupling between the ligand PTH and the C-terminal helix α5 of the Gα subunit controls the stability of the PTH1R complex with the specific G protein, G_s or G_q. Single-cell-level experiments further validate the G protein-selective effects of the PTH binding pose by demonstrating the differential, G protein-dependen

SUBMITTER: Zhang X 

PROVIDER: S-EPMC12002267 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature