Endogenous ligand recognition and structural transition of a human PTH receptor

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 activatio...

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Veröffentlicht in:Molecular cell 2022-09, Vol.82 (18), p.3468-3483.e5
Hauptverfasser: Kobayashi, Kazuhiro, Kawakami, Kouki, Kusakizako, Tsukasa, Miyauchi, Hirotake, Tomita, Atsuhiro, Kobayashi, Kan, Shihoya, Wataru, Yamashita, Keitaro, Nishizawa, Tomohiro, Kato, Hideaki E., Inoue, Asuka, Nureki, Osamu
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Sprache:eng
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Zusammenfassung: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. [Display omitted] •Cryo-EM structures of PTH-PTH1R-Gs and PTHrP-PTH1R-Gs complex•Structural basis of the affinity and selectivity of PTH1R endogenous ligands•Sequential activation mechanism of the PTH1R by endogenous ligands•Structural changes in the PTH-PTH1R-Gs complex triggered by the ligand dissociation The six distinct structures of PTH-PTH1R-Gs and PTHrP-PTH1R-Gs reveal the differential endogenous ligand recognition and dynamic conformational change in both the extracellular and intracellular regions. These structures and molecular dynamics simulations provide a ligand dissociation mechanism from the receptor and illuminate the distinct signal durations induced by PTH and PTHrP.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2022.07.003