The parathyroid hormone type 1 receptor (PTHR1), a Class B GPCR, is activated by long polypeptides, including drugs for osteoporosis and hypoparathyroidism. The PTHR1 engages peptide agonists via a two-step mechanism. Initial contact involves the extracellular domain (ECD), which has been thought to contribute primarily to receptor–peptide binding, and then the N terminus of the peptide engages the receptor transmembrane domain (TMD), which is thought to control the message conveyed to intracellular partners. This mechanism has been suggested to apply to other Class B GPCRs as well. Here, we show that modification of a PTHR1 agonist at ECD-contact sites can alter the signaling profile, an outcome that is not accommodated by the current two-step binding model. Our data support a modified two-step binding model in which agonist orientation on the ECD surface can influence the geometry of agonist–TMD engagement. This expanded binding model offers a mechanism by which altering ECD-contact residues can affect signaling profile. Our discoveries provide a rationale for exploring agonist modifications distal from the TMD-contact region in future efforts to optimize therapeutic performance of peptide hormone analogs.

中文翻译：

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通过修饰的激动剂与细胞外结构域的接触改变 PTH 受体的信号提供了在体内延长激动作用的途径

甲状旁腺激素 1 型受体 (PTHR1) 是一种 B 类 GPCR，由长多肽激活，包括治疗骨质疏松症和甲状旁腺功能减退症的药物。PTHR1 通过两步机制与肽激动剂结合。最初的接触涉及细胞外结构域 (ECD)，它被认为主要有助于受体-肽结合，然后肽的 N 末端与受体跨膜结构域 (TMD) 结合，它被认为控制传递到细胞内的信息伙伴。这种机制也被建议应用于其他 B 类 GPCR。在这里，我们展示了在 ECD 接触位点修改 PTHR1 激动剂可以改变信号传导概况，这是当前两步结合模型无法适应的结果。我们的数据支持改进的两步结合模型，其中 ECD 表面上的激动剂方向可以影响激动剂-TMD 接合的几何形状。这种扩展的结合模型提供了一种机制，通过该机制改变 ECD 接触残基可以影响信号转导谱。我们的发现为探索远离 TMD 接触区域的激动剂修饰提供了理论依据，以在未来优化肽激素类似物的治疗性能。