ANP RECEPTOR STRUCTURE AND SIGNALING

ANP 受体结构和信号传导

• 批准号: 7369487
• 负责人: KUNIO S MISONO
• 金额: $ 0.13万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7369487
• 关键词: ANP; RECEPTOR; STRUCTURE; SIGNALING

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Atrial natriuretic peptide (ANP) is a cardiac hormone that stimulates salt excretion and dilates blood vessels. ANP plays a major role in blood pressure and salt-fluid volume regulation, and anomaly in its activities may cause heart failure, hypertension, and other cardiovascular diseases. ANP activities are mediated by a specific cell membrane receptor coupled to its intrinsic guanylate cyclase (GCase) activity. The receptor functions as a dimer of a single-span transmembrane protein, each consisting of an extracellular ANP-binding domain and an intracellular GCase catalytic domain. ANP binding to the extracellular domain activates GCase catalysis by an yet unknown mechanism. Our aims are to determine the structure of ANP receptor and to elucidate the mechanisms of receptor-hormone binding and transmembrane signaling. During the past year, we determined the crystal structure of the extracellular domain of the receptor (ANPR) in complex with the hormone ANP. By the structural comparison with the apo-receptor structure that we determined previously, we have identified a structural basis for ANP receptor signaling. We have found a unique hormone-induced rotation motion of the two juxtamembrane domains in the receptor dimmer that apparently initiates transmembrane signal transduction. Additionally, w have determine the crystal structure of the ANPR containing a non-covalently associated bromide ion (instead of chloride ion in the native receptor) (manuscript in preparation). We also have obtained preliminary structures of two constitutively active ANPR mutants. These studies will provide better understanding of the mechanism of ANP and ANP interaction, receptor activation, and regulation. Such knowledge will lead to more accurate diagnosis methods and effective treatments for cardiovascular diseases. These studies will also facilitate development of drugs targeted at the ANP receptor via structure-based drug design. Those drugs will be useful in treating heart failure, hypertension, and other cardiovascular diseases.An

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。心钠素（ANP）是一种心脏激素，可刺激盐分排泄并扩张血管。 ANP在血压和盐液容量调节中发挥着重要作用，其活动异常可能导致心力衰竭、高血压等心血管疾病。 ANP 活性由与其内在鸟苷酸环化酶 (GCase) 活性偶联的特定细胞膜受体介导。该受体作为单跨跨膜蛋白的二聚体发挥作用，每个二聚体由胞外 ANP 结合结构域和胞内 GCase 催化结构域组成。 ANP 与胞外结构域的结合通过一种尚不清楚的机制激活 GCase 催化作用。我们的目标是确定 ANP 受体的结构并阐明受体-激素结合和跨膜信号传导的机制。在过去的一年里，我们确定了与激素 ANP 复合的受体 (ANPR) 胞外结构域的晶体结构。通过与我们之前确定的apo受体结构进行结构比较，我们已经确定了ANP受体信号传导的结构基础。我们发现受体二聚体中两个近膜结构域有一种独特的激素诱导的旋转运动，这显然启动了跨膜信号转导。此外，我们还确定了含有非共价结合的溴离子（而不是天然受体中的氯离子）的 ANPR 的晶体结构（手稿正在准备中）。我们还获得了两个具有组成型活性的 ANPR 突变体的初步结构。这些研究将有助于更好地理解 ANP 和 ANP 相互作用、受体激活和调节的机制。这些知识将为心血管疾病带来更准确的诊断方法和有效的治疗方法。这些研究还将通过基于结构的药物设计促进针对 ANP 受体的药物的开发。这些药物将有助于治疗心力衰竭、高血压和其他心血管疾病。