High-resolution crystal structure of parathyroid hormone 1 receptor in complex with a peptide agonist
High-resolution crystal structure of parathyroid hormone 1 receptor in complex with a peptide agonist
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DOI：
10.1038/s41594-018-0151-4
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发表时间：
2018-12-01
影响因子：
16.8
通讯作者：
Plueckthun, Andreas
中科院分区：
文献类型：
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作者：
Ehrenmann, Janosch;Schoeppe, Jendrik;Plueckthun, Andreas
甲状旁腺激素1受体（PTH1R）是一种控制钙稳态的B类多结构域g蛋白偶联受体（GPCR）。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），激活受体，它们的类似物teriparatide和abaloparatide在临床中用于增加骨形成，作为一种有效但昂贵的骨质疏松症治疗方法。PTH1R的激活涉及肽配体与受体胞外结构域（ECD）和跨膜结构域（TMD）的结合，这是B类gpcr的标志。在这里，我们在2.5埃分辨率下展示了人类PTH1R与肽激动剂复合物的晶体结构，使我们能够描绘出这种受体的激动剂结合模式，并揭示了保守结构基序中的分子细节，这些结构基序对B类受体的功能至关重要。因此，本研究提供了对PTH1R功能的结构洞察，并扩展了我们对这类具有重要治疗意义的gpcr的理解。
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-angstrom 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.