Endogenous ligand recognition and structural transition of a human PTH receptor
Endogenous ligand recognition and structural transition of a human PTH receptor
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DOI：
10.1016/j.molcel.2022.07.003
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发表时间：
2022-09-15
期刊：
影响因子：
16
通讯作者：
Nureki, Osamu
中科院分区：
文献类型：
--
作者：
Kobayashi, Kazuhiro;Kawakami, Kouki;Nureki, Osamu
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（PTH 1 R）结合并激活刺激性G蛋白（Gs）信号通路。有趣的是，这两种锂离子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，降低骨吸收作用。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存在下六种形式的人PTH 1 R-Gs复合物的冷冻电子显微镜结构，分辨率为2.8 - 4.1。PTH结合和PTHrP结合结构的比较揭示了不同的配体-受体相互作用的配体亲和力和选择性。此外，五种不同的PTH结合结构，结合计算分析，提供了独特的和复杂的配体从受体解离过程的见解，并阐明了PTH和PTHrP诱导的信号传导的不同持续时间。
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.