The structural basis of the interaction of human relaxins with their receptors.

人类基因2(H2)松弛素是一种结构上与胰岛素相关的多肽激素，在妊娠过程中具有许多与其作用相关的生物学作用。它主要通过诱导胶原蛋白的分解和新血管的形成来发挥这些作用，同时刺激组织生长和抑制细胞死亡。它的功能已经导致了松弛素的几个潜在的治疗作用被探索。这些包括纤维疾病和外周血管疾病的治疗。H2松弛素是体内的主要表达产物，已被证明除了通常与怀孕有关的生理反应外，还具有广泛的生理反应。我们最近发现了另一种主要在大脑中表达的人类-H3-松弛素，这强烈表明了神经肽的作用。令人惊讶的是，H2和3松弛蛋白各自通过不同的G蛋白偶联受体发挥作用。我们将进行详细的结构-功能研究，以确定这些松弛蛋白是如何赋予它们特定的生物学作用的。将使用现代化学合成方案来制备这些复杂多肽中的每一个，以进行详细的二级和三级结构研究。将制备含有修饰残基和全局结构域的类似物，并对其特征松弛素激动剂和拮抗剂活性进行检测。复杂的生物分子相互作用分析将被用来识别这两种松弛素受体结合区的差异。这些结果，再加上核磁共振三维结构分析的结果，将使我们最终确定H2和3激素的关键特征，这些激素负责选择性受体结合和特定的松弛活性。然后，我们将能够设计出更小、更稳定、具有口服活性的松弛素类药物。这些化合物将在治疗纤维化或作为松弛作用的生物和药理探针方面具有巨大的应用潜力。

Human Gene 2 (H2) relaxin is a peptide hormone structurally related to insulin and has numerous biological actions related to its roles during pregnancy. It exerts these primarily by inducing the breakdown of collagen and the formation of new blood vessels while simultaneously stimulating tissue growth and inhibiting cell death. Its functions have led to several potential therapeutic roles for relaxin being explored. These include the treatment of fibrotic disorders and peripheral vascular disease. H2 relaxin is the principal expression product in vivo and has been shown to exert a wide range of physiological responses beyond those normally associated with pregnancy. We have recently discovered another human - H3 - relaxin that is expressed primarily in the brain which strongly suggests a neuropeptide role. Surprisingly, H2 and 3 relaxins each act via different G-protein coupled receptors. We will perform detailed structure-function studies to determine how these relaxins impart their specific biological actions. Modern chemical synthesis protocols will be used to prepare each of these complex peptides in adequate quantities for detailed secondary and tertiary structural study. Analogues containing modified residues and global domains will be prepared and assayed for characteristic relaxin agonist and antagonist activity. Sophisticated biomolecular interaction analyses will be used to identify differences in receptor binding regions for the two relaxins. The results, together with those obtained by three-dimensional structural analysis using NMR spectroscopy, will allow us to ultimately define the key features of the H2 and 3 hormones that are responsible for selective receptor binding and specific relaxin activity. We will then be able to design smaller, more stable, orally active relaxin mimetics. Such compounds will have great potential for therapeutic application in the treatment of fibrosis or as biological and pharmacological probes of relaxin action.