INTERACTION BETWEEN PARATHYROID HORMONE AND ITS RECEPTOR

甲状旁腺激素与其受体之间的相互作用

• 批准号: 6062458
• 负责人: ROBERT C GENSURE
• 金额: $ 4.43万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6062458
• 关键词: SDS polyacrylamide gel electrophoresis; affinity labeling; autoradiography; crosslink; high performance liquid chromatography; hormone receptor; inhibitor /antagonist; mass spectrometry; parathyroid hormone related protein; parathyroid hormones; protein protein interaction; receptor binding; reversed phase chromatography; site directed mutagenesis

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.

我建议研究甲状旁腺激素 (PTH) 和 PTH 相关肽 (PTHrP) 与三种 G 蛋白偶联受体的相互作用，即 PTH/PTHrP 受体 (P1R)、新发现的 PTH-2 受体 (P2R) 以及最近在斑马鱼中描述的第三种 PTH 受体 (P3R)。 P1R 和 P2R 以同样高的亲和力结合 PTH 和 PTHrP。 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非常重要。 因此，将进行光亲和交联研究来定义与 PTH/PTHrP 羧基末端相互作用的受体区域。然后使用受体的定点诱变来鉴定与每个配体相互作用的各个受体残基。 因此，这些研究将尝试定义负责与 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。 获得的信息将有助于非肽激动剂和/或拮抗剂的开发，这些激动剂和/或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症和甲状旁腺功能减退症方面具有临床意义。