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.

内源性甲状旁腺激素 (PTH) 和 PTH 相关肽 (PTHrP) 与甲状旁腺激素受体 1 (PTH1R) 结合并激活刺激性 G 蛋白 (Gs) 信号通路。有趣的是，这两种配体具有不同的信号传导和生理特性：PTH 引起延长的 Gs 激活，而 PTHrP 引起短暂的 Gs 激活并降低骨吸收效应。不同的分子作用归因于配体识别和解离动力学的差异。在这里，我们报告了在 PTH 或 PTHrP 存在下，人类 PTH1R-Gs 复合物的六种形式的低温电子显微结构，分辨率为 2.8 –4.1 Å。PTH 结合和 PTHrP 结合结构的比较揭示了配体亲和力和选择性的不同配体-受体相互作用。此外，五种不同的 PTH 结合结构，