The molecular mechanism of relaxin receptor signaling

松弛素受体信号传导的分子机制

• 批准号: 9906240
• 负责人: Sarah Cecilia Erlandson
• 金额: $ 3.32万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906240
• 关键词: Acute; Address; Affinity; Agonist; Binding; Biological; Cardiovascular Diseases; Cell Line; Cell Surface Receptors; Clinical Trials; Collaborations; Cryoelectron Microscopy; Disease; Drug Design; Drug Targeting; Engineering; Extracellular Matrix; Family; Fibrosis; Future; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Gene Expression; Genetic Transcription; Heart; Heart Diseases; Heart failure; Hormones; Human; Immunoglobulin Fragments; Investigation; Kidney; Label; Lead; Leucine-Rich Repeat; Ligand Binding; Ligands; Lipids; Liver; Low-Density Lipoproteins; Mass Spectrum Analysis; Mediating; Methods; Molecular; Organ; Pathway interactions; Peptides; Phase; Physiology; Protein Engineering; Proteins; Receptor Activation; Receptor Signaling; Recombinants; Relaxin; Research; Signal Pathway; Signal Transduction; Structure; Surface; System; Techniques; Tissues; Translating; Transmembrane Domain; Vasodilation; X-Ray Crystallography; Yeasts; analog; angiogenesis; base; drug development; experimental study; improved; insight; interest; medical schools; nanobodies; novel; novel therapeutics; peptide hormone; protein protein interaction; receptor; receptor binding; relaxin receptor; response; small molecule; structured data; targeted treatment; therapeutic target; tool; transcriptome sequencing

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.

抽象。 G蛋白偶联受体（GPCR）构成细胞表面受体的最大家族之一， 调节人体生理的许多方面。松弛素受体RXFP 1是一种知之甚少的GPCR， 其目前在临床试验中作为急性心力衰竭的疗法。在这些试验中，RXFP 1是 由其内源性激动剂小蛋白激素松弛素-2的重组版本激活。结合 松弛素-2对RXFP 1诱导多效性细胞反应，包括血管舒张、血管生成和 细胞外基质重塑这些影响在各种组织，特别是心脏，肝脏和肾脏，使 RXFP 1是治疗心血管疾病和多种器官纤维化疾病的一个很有前途的药物靶点。 尽管RXFP 1具有重要的生物学意义，但对RXFP 1的详细机制知之甚少。 松弛素-2的受体激活。 RXFP 1属于富含亮氨酸重复序列的GPCR（LGR）家族，这是由于其大的胞外域， 含有10个富含亮氨酸的重复序列（LRR）和N-末端的低密度脂蛋白A型模块。的 这些将松弛素-2结合与细胞内信号传导偶联的结构域之间的相互作用是未知的， 这主要是因为缺乏结构性数据。因此，我将确定与松弛素-2结合的RXFP 1的结构， 这将揭示参与配体结合和信号转导的相互作用， 未来基于结构的药物设计第二个关键目标集中在这样一个事实，即有很少的配体 可用于调节RXFP1信号传导。因此，目前不可能将RXFP 1信令或 选择性地激活受体信号通路的特定子集。缺乏合适的研究工具 RXFP 1激活及其细胞后果阻碍了我们对该受体分子的理解 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， 通过蛋白质工程的RXPF 1拮抗剂。表征这些配体调节 RXFP 1的细胞反应将为受体的信号传导机制提供新的见解， 生成可用于药物开发的信息。总体而言，拟议的研究将 从而更好地理解RXFP 1信号传导的分子机制，并将提高我们的能力， 将对RXFP1的生物医学兴趣转化为新的治疗方法。