Department of Biochemistry, University of Zürich, Zurich, Switzerland.
Sosei Heptares, Granta Park, Cambridge, UK.
Nat Struct Mol Biol. 2018 Dec;25(12):1086-1092. doi: 10.1038/s41594-018-0151-4. Epub 2018 Nov 19.
Parathyroid hormone 1 receptor (PTH1R) is a class B multidomain G-protein-coupled receptor (GPCR) that controls calcium homeostasis. Two endogenous peptide ligands, parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP), activate the receptor, and their analogs teriparatide and abaloparatide are used in the clinic to increase bone formation as an effective yet costly treatment for osteoporosis. Activation of PTH1R involves binding of the peptide ligand to the receptor extracellular domain (ECD) and transmembrane domain (TMD), a hallmark of class B GPCRs. Here, we present the crystal structure of human PTH1R in complex with a peptide agonist at 2.5-Å resolution, allowing us to delineate the agonist binding mode for this receptor and revealing molecular details within conserved structural motifs that are critical for class B receptor function. Thus, this study provides structural insight into the function of PTH1R and extends our understanding of this therapeutically important class of GPCRs.
甲状旁腺激素 1 型受体（PTH1R）是一种 B 类多结构域 G 蛋白偶联受体（GPCR），它控制着钙的动态平衡。两种内源性肽配体，甲状旁腺激素（PTH）和甲状旁腺激素相关蛋白（PTHrP），可以激活该受体，它们的类似物特立帕肽和abaloparatide 被用于临床中，作为一种有效的、但昂贵的骨质疏松症治疗方法，增加骨形成。PTH1R 的激活涉及到肽配体与受体细胞外结构域（ECD）和跨膜结构域（TMD）的结合，这是 B 类 GPCR 的标志。在这里，我们以 2.5-Å 的分辨率呈现了人 PTH1R 与肽激动剂复合物的晶体结构，使我们能够描绘该受体的激动剂结合模式，并揭示对于 B 类受体功能至关重要的保守结构基序内的分子细节。因此，这项研究为 PTH1R 的功能提供了结构上的见解，并扩展了我们对这一治疗上重要的 GPCR 类别的理解。
