The parathyroid hormone (PTH) 1 receptor (PTH1R) is a G protein-coupled receptor (GPCR) that regulates skeletal development and calcium homeostasis. Here, we describe cryo-EM structures of the PTH1R in complex with fragments of the two hormones, PTH and PTH-related protein, the drug abaloparatide, as well as the engineered tool compounds, long-acting PTH (LA-PTH) and the truncated peptide, M-PTH(1–14). We found that the critical N terminus of each agonist engages the transmembrane bundle in a topologically similar fashion, reflecting similarities in measures of Gαs activation. The full-length peptides induce subtly different extracellular domain (ECD) orientations relative to the transmembrane domain. In the structure bound to M-PTH, the ECD is unresolved, demonstrating that the ECD is highly dynamic when unconstrained by a peptide. High resolutions enabled identification of water molecules near peptide and G protein binding sites. Our results illuminate the action of orthosteric agonists of the PTH1R.

甲状旁腺激素 (PTH) 1 受体 (PTH1R) 是一种 G 蛋白偶联受体 (GPCR)，可调节骨骼发育和钙稳态。在这里，我们描述了 PTH1R 的低温电子显微镜结构，它与两种激素、 PTH和 PTH 相关蛋白的片段、药物阿巴拉肽以及工程工具化合物、长效 PTH (LA-PTH) 和截短肽，M-PTH(1–14)。我们发现关键的 N 末端每个激动剂以拓扑相似的方式参与跨膜束，反映了 Gαs 激活测量的相似性。全长肽诱导相对于跨膜结构域的细胞外结构域 (ECD) 方向略有不同。在与 M-PTH 结合的结构中，ECD 未解析，表明 ECD 在不受肽约束时具有高度动态性。高分辨率能够识别肽和 G 蛋白结合位点附近的水分子。我们的结果阐明了 PTH1R 正构激动剂的作用。