INTERACTION BETWEEN PARATHYROID HORMONE AND ITS RECEPTOR

甲状旁腺激素与其受体之间的相互作用

基本信息

批准号：
6402575
负责人：
ROBERT C GENSURE
金额：
$ 4.94万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-07-01 至 2002-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6402575
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

项目摘要

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）和与PTH相关的肽（PTHRP）与三个G蛋白偶联受体，（P1R）的PTH/PTHRP受体（P1R）（新发现的PTH-2受体（P2R）（P2R）的PTH/PTHRP受体，以及最近在Zebraf中描述的第三个PTH受体（P2R）。 P1R和P2R结合具有同样高亲和力的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至关重要。因此，将进行光性交联研究，以定义与PTH/PTHRP的羧基末端相互作用的受体区域。然后将使用位置定向的受体诱变来识别与每个配体相互作用的单个受体残基。因此，这些研究将试图定义负责高亲和力与PTH和PTHRP的特定残基，有助于确定P2R和P3R如何区分两个配体之间。获得的信息将有助于开发非肽激动剂和/或拮抗剂，这些动力和/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腺功能低下。