AI Article Synopsis
- Endogenous parathyroid hormone (PTH) and PTH-related peptide (PTHrP) both activate the parathyroid hormone receptor 1 (PTH1R) through the Gs signaling pathway, but they have unique effects on signaling duration and bone-resorption activities.
- Structural analysis via cryoelectron microscopy has revealed six forms of the PTH1R-Gs complex, highlighting differences in how PTH and PTHrP interact with the receptor.
- The study of these structures, along with computational methods, enhances our understanding of the distinct mechanisms behind ligand binding and dissociation, which explains PTH's prolonged effects versus PTHrP's more transient signaling.
Article Abstract
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 ligands 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 Å. 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 process of ligand dissociation from the receptor and shed light on the distinct durations of signaling induced by PTH and PTHrP.
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| http://dx.doi.org/10.1016/j.molcel.2022.07.003 | DOI Listing |
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