The molecular mechanism of relaxin receptor signaling

抽象的。 G蛋白偶联受体(GPCRs)是最大的细胞表面受体家族之一。 调节人体生理的多个方面。松弛素受体RXFP1是一种知之甚少的gpcr 目前正在进行临床试验，作为治疗急性心力衰竭的靶点。在这些试验中，RXFP1是 被其内源性激动剂的重组版本激活，小蛋白激素松弛素-2。约束： 松弛素-2对RXFP1诱导多效性细胞反应，包括血管扩张，血管生成，和 细胞外基质重塑。这些作用在各种组织中，特别是心脏、肝脏和肾脏，使 RXFP1是治疗心血管疾病和多种器官纤维化疾病的有前途的药物靶点。 尽管RXFP1具有重要的生物学意义，但人们对RXFP1的详细机制知之甚少 松弛素-2激活受体。 RXFP1因其较大的胞外结构域而属于富含亮氨酸重复序列的GPCR(LGR)家族。 包含10个富含亮氨酸的重复序列(LRR)和N末端的一个低密度脂蛋白A型模块。这个 松弛蛋白-2结合到细胞内信号的这些结构域之间的相互作用尚不清楚， 这在很大程度上是因为缺乏结构性数据。因此，我将确定与松弛蛋白-2结合的RXFP1的结构， 它将揭示参与配体结合和信号转导的相互作用，为 未来基于结构的药物设计。第二个关键目标集中于这样一个事实，即配体非常少 可用于调制RXFP1信令。因此，目前无法停用RXFP1信令或 选择性地激活受体信号通路的特定亚群。缺乏合适的研究工具 RXFP1的激活及其细胞后果阻碍了我们对该受体分子的理解 作用机制和作为治疗靶点的全部潜力。为了解决这个问题，我将开发新的激动剂和 通过蛋白质工程研究RXPF1的拮抗剂。这些配体的调节能力的表征 S的细胞反应将为了解受体的信号机制提供新的见解 产生可用于药物开发的信息。总的来说，拟议的研究将 使我们更好地理解RXFP1信号的分子机制，并将提高我们的能力 将生物医学对RXFP1的兴趣转化为新的治疗方法。

Abstract. G protein-coupled receptors (GPCRs) constitute one of the largest families of cell surface receptors and regulate many aspects of human physiology. The relaxin receptor, RXFP1, is a poorly understood GPCR which is currently being targeted in clinical trials as a therapy for acute heart failure. In these trials, RXFP1 is activated by a recombinant version of its endogenous agonist, the small protein hormone relaxin-2. Binding of relaxin-2 to RXFP1 induces pleiotropic cellular responses, including vasodilation, angiogenesis, and extracellular matrix remodeling. These effects in various tissues, particularly the heart, liver, and kidneys, make RXFP1 a promising drug target to treat cardiovascular diseases and multiple diseases of organ fibrosis. Despite the biological importance of RXFP1, relatively little is known about the detailed mechanisms underlying receptor activation by relaxin-2. RXFP1 belongs to the leucine-rich repeat-containing GPCR (LGR) family due to its large ectodomain, which contains ten leucine-rich repeats (LRRs) and a low-density lipoprotein type A module at the N-terminus. The interactions between these domains which couple relaxin-2 binding to intracellular signaling are unknown, largely due to a lack of structural data. Therefore, I will determine the structure of RXFP1 bound to relaxin-2, which will reveal the interactions involved in ligand binding and signal transduction to provide information for future structure-based drug design. A second key objective focuses on the fact that there are very few ligands available to modulate RXFP1 signaling. As a result, it is currently not possible to inactivate RXFP1 signaling or selectively activate specific subsets of the receptor's signaling pathways. The lack of suitable tools to study RXFP1 activation and its cellular consequences have hindered our understanding of the receptor's molecular mechanism and full potential as a therapeutic target. To address this, I will develop novel agonists and antagonists of RXPF1 through protein engineering. Characterization of the ability of these ligands to modulate RXFP1's cellular responses will provide new insights into the receptor's signaling mechanisms and will generate information which can be leveraged for drug development. Collectively, the proposed research will lead to a better understanding of the molecular mechanism of RXFP1 signaling and will improve our ability to translate biomedical interest in RXFP1 into new therapeutics.