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，是一种重要的药物靶点 由于其在介导两种相关内分泌肽激素的不同生物学作用中的作用， 降钙素（CT）和胰淀素（AMY）。CT通过信号传导调节钙稳态和骨转换 通过CTR。AMY通过异二聚体复合物的信号传导调节血糖水平。 CTR和三种相关的受体活性修饰蛋白（RAMP）中的任何一种，其作为共受体， 改变AMR的CTR特异性。激素的合成类似物对CT和AMY受体的激动作用 分别用于治疗骨质疏松症和I型和II型糖尿病。尽管CT的临床价值和 AMY受体激动、CTR激素结合的分子机制和RAMP介导的改变 由于缺乏CTR激素特异性的结构信息， 受体复合物。CT和AMY的结合亲和力和特异性在很大程度上由以下因素决定： CTR和RAMP整合膜蛋白的胞外结构域（ECDs）。这个的目标 建议是表征受体ECD的相互作用，并确定晶体结构， 可溶性CT-和Amy-受体ECD复合物。结果将确定CT和AMY的分子基础 结合其受体ECDs，描绘RAMPs如何改变CTR的激素特异性，并提供 结构模板来指导针对受体的优化疗法的设计。我们建议 （1）确定人CTR ECD识别CT的分子机制。 在这一目标中产生的晶体结构将定义人类和鲑鱼CT激素如何结合到 CTR并有助于开发用于治疗骨质疏松症的疗法。(2)确定结构和 CTR和RAMP ECD相互作用的功能基础。得到的CTR ECD-RAMP ECD 异二聚体结构将揭示AMY受体的分子结构。(3)测定分子 AMY与CTR ECD-RAMP ECD异二聚体结合的机制。实现这一目标将决定一个 RAMP改变CTR的激素特异性，并有助于糖尿病治疗的设计。

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.