期刊
MOLECULAR CELL
卷 82, 期 18, 页码 3468-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2022.07.003
关键词
-
资金
- JSPS KAKENHI [20J21820, 19H03163, 21H05142, 16H06294, 21H04791, 21H05113, JPJSBP120213501, JPJSBP120218801]
- Inamori Foundation
- Japan Agency for Medical Research and Development (AMED) [JP20gm0010004, JP20am0101095, JPMJFR215T]
- FOREST Program [JPMJMS2023]
- Japan Science and Technology Agency (JST)
- [19gm5910013]
This study reports the cryoelectron microscopic structures of the human PTH1R-Gs complex in the presence of endogenous parathyroid hormone and PTH-related peptide, revealing distinct ligand-receptor interactions and signaling durations induced by these two ligands.
Endogenous parathyroid hormone (PTH) and PTH-related peptide (PTHrP) bind to the parathyroid hormone receptor 1 (PTH1R) and activate the stimulatory G-protein (Gs) signaling pathway. Intriguingly, the two li-gands have distinct signaling and physiological properties: PTH evokes prolonged Gs activation, whereas PTHrP evokes transient Gs activation with reduced bone-resorption effects. The distinct molecular actions are ascribed to the differences in ligand recognition and dissociation kinetics. Here, we report cryoelectron microscopic structures of six forms of the human PTH1R-Gs complex in the presence of PTH or PTHrP at resolutions of 2.8 -4.1 A. A comparison of the PTH-bound and PTHrP-bound structures reveals distinct ligand-receptor interactions underlying the ligand affinity and selectivity. Furthermore, five distinct PTH-bound structures, combined with computational analyses, provide insights into the unique and complex pro-cess of ligand dissociation from the receptor and shed light on the distinct durations of signaling induced by PTH and PTHrP.
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