ANP RECEPTOR STRUCTURE AND SIGNALING

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 心房利钠肽（ANP）是一种心脏激素，刺激盐排泄和扩张血管。ANP在血压和盐液容量调节中起重要作用，其活性异常可引起心力衰竭、高血压等心血管疾病。ANP活性由与其内在鸟苷酸环化酶（GCase）活性偶联的特异性细胞膜受体介导。 该受体作为单跨膜蛋白的二聚体起作用，每个二聚体由细胞外ANP结合结构域和细胞内GCase催化结构域组成。ANP与细胞外结构域的结合通过一种未知的机制激活GCase催化。本研究的目的是确定心钠素受体的结构，阐明受体与激素结合及跨膜信号转导的机制。 在过去的一年中，我们确定了与激素ANP复合的受体（ANPR）的胞外结构域的晶体结构。 通过与我们先前确定的脱辅基受体结构的结构比较，我们已经确定了ANP受体信号传导的结构基础。 我们已经发现了一个独特的双螺旋诱导的旋转运动的两个跨膜结构域的受体二聚体，显然启动跨膜信号转导。 此外，我们已经确定了含有非共价缔合的溴离子（而不是天然受体中的氯离子）的ANPR的晶体结构（手稿在准备中）。 我们还获得了两个组成型活性ANPR突变体的初步结构。 这些研究将有助于更好地了解ANP及其相互作用、受体激活和调节的机制。 这些知识将导致更准确的诊断方法和有效的治疗心血管疾病。 这些研究还将促进通过基于结构的药物设计开发针对ANP受体的药物。 这些药物将可用于治疗心力衰竭、高血压和其他心血管疾病。

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