INTERACTION BETWEEN PARATHYROID HORMONE AND ITS RECEPTOR

我建议研究甲状旁腺激素（PTH）和PTH相关肽（PTHrP）与三种g蛋白偶联受体，PTH/PTHrP受体（P1R），新发现的PTH-2受体（P2R）和最近在斑马鱼中发现的第三种PTH受体（P3R）的相互作用。P1R和P2R结合PTH和PTHrP具有同样高的亲和力。P2R优先结合PTH，而P3R优先结合PTHrP。已知PTH/PTHrP的羧基末端对于与这些受体的高亲和力结合是重要的。因此，将进行光亲和交联研究，以确定与PTH/PTHrP的羧基端相互作用的受体区域。受体的定点诱变将用于鉴定与每个配体相互作用的单个受体残基。因此，这些研究将试图确定与PTH和PTHrP高亲和力结合的受体结构域和特定残基，帮助确定P2R和P3R如何区分这两种配体。所获得的信息将有助于开发非肽激动剂和/或拮抗剂，这些拮抗剂可能在治疗骨质疏松症或各种形式的甲状旁腺功能亢进和甲状旁腺功能低下方面具有临床意义。

I propose to investigate the interaction of parathyroid hormone (PTH) and PTH-related peptide (PTHrP) with three G-protein-coupled receptors, the PTH/PTHrP receptor for (P1R), the newly discovered PTH-2 receptor (P2R), and the third PTH receptor (P3R) recently described in zebrafish. P1R and P2R bind PTH and PTHrP with equally high affinity. P2R binds PTH preferentially, while P3R binds preferentially, to PTHrP. The carboxy terminus of PTH/PTHrP is known to be important for high affinity binding to these receptors. Photoaffinity cross-linking studies will therefore be performed to define receptor regions that interact with the carboxy-terminus of PTH/PTHrP. Site-directed mutagenesis of the receptors will then be used to identify individual receptor residues that interact with each ligand. These studies will thus attempt to define the receptor domains and specific residues responsible for high affinity binding to PTH and PTHrP, helping to determine how P2R and P3R distinguish between the two ligands. The information obtained will aid in the development of nonpeptide agonists and/or antagonists that may gain clinical significance in treating osteoporosis or the various forms of hyperparathyroidism and hypoparathyroidism.