Hormone Recognition by the Calcitonin and Amylin Receptors

人降钙素受体(CTR)是一种G蛋白偶联受体，是重要的药物靶点 由于它在调节两种相关的内分泌肽激素的不同生物学作用方面发挥了作用， 降钙素(CT)和胰淀素(AMY)。CT通过信号转导调节钙稳态和骨转换 通过CTR。AMY通过一种异二聚体复合体调节血糖水平 CTR和作为辅受体的三种相关受体活性修饰蛋白(RAMP)中的任何一种 更改艾米的CTR特异性。合成激素类似物对CT和AMY受体的兴奋作用 分别用于治疗骨质疏松症和I型和II型糖尿病。尽管CT和CT的临床价值 AMY受体激动性、CTR激素结合和RAMP介导改变的分子机制 由于缺乏CTR激素特异性的结构信息，人们对其知之甚少 激素受体复合体。CT和AMY结合的亲和力和特异性在很大程度上取决于 CTR和RAMP膜蛋白的胞外区(ECDs)。这样做的目的是 建议表征激素-受体ECD相互作用并确定其晶体结构 可溶性CT和AMY受体ECD复合体。这些结果将确定CT和AMY的分子基础 与其受体ECDs结合，描绘RAMP如何改变CTR的激素特异性，并提供 结构模板，用于指导针对受体的优化治疗药物的设计。我们建议 主要研究内容如下：(1)确定人CTR-ECD识别CT的分子机制。 在这个目标中产生的晶体结构将定义人类和鲑鱼CT激素如何与 CTR，并帮助开发治疗骨质疏松症的疗法。(2)确定结构和 CTR和RAMP ECDs相互作用的功能基础。由此产生的CTR ECD-RAMP ECD 异二聚体结构将揭示AMY受体的分子结构。(3)确定分子 AMY与CTR ECD-RAMP ECD异源二聚体结合的机制。实现这一目标将定义如何 RAMP改变了CTR的激素特异性，并有助于糖尿病治疗药物的设计。

The human calcitonin receptor (CTR) is a G protein-coupled receptor that is an important drug target because of its role in mediating the distinct biological actions of two related endocrine peptide hormones, calcitonin (CT) and amylin (AMY). CT regulates calcium homeostasis and bone turnover by signaling through the CTR. AMY regulates blood glucose levels by signaling through a heterodimeric complex ofthe CTR and any one of three related receptor activity modifying proteins (RAMPs) that act as co-receptors to alter CTR specificity for AMY. Agonism of the CT and AMY receptors by synthetic analogs of the hormones is used to treat osteoporosis and types I and II diabetes, respectively. Despite the clinical value of CT and AMY receptor agonism, the molecular mechanisms of CTR hormone binding and RAMP-mediated alteration of CTR hormone specificity are poorly understood because of a lack of structural information for the hormone-receptor complexes. CT and AMY binding affinity and specificity are in large part determined by the extracellular domains (ECDs) ofthe CTR and RAMP integral membrane proteins. The goals of this proposal are to characterize the hormone-receptor ECD interactions and to determine crystal structures of soluble CT- and AMY-receptor ECD complexes. The results will define the molecular bases for CT and AMY binding to their receptor ECDs, delineate how RAMPs alter hormone specificity ofthe CTR, and provide structural templates to guide the design of optimized therapeutics targeting the receptors. We propose the following three aims: (1) Determine the molecular mechanism of CT recognition by the human CTR ECD. The crystal structures generated in this aim will define how human and salmon CT hormones bind to the CTR and aid the development of therapeutics for treating osteoporosis. (2) Determine the structural and functional bases for interaction ofthe CTR and RAMP ECDs. The resulting CTR ECD-RAMP ECD heterodimer structure will reveal the molecular architecture of an AMY receptor. (3) Determine the molecular mechanism of AMY binding to a CTR ECD-RAMP ECD heterodimer. Achieving this aim will define how a RAMP alters the hormone specificity of the CTR and aid the design of therapeutics for diabetes.