Structure-function and domain minimization of insulin-like peptide 3, a novel member of the insulin superfamily.

胰岛素样肽3 （INSL3）是一种结构类似于胰岛素的肽激素。它在睾丸和卵巢中产生。在男性中，它的主要作用之一是在胎儿发育期间通过对脐韧带的直接作用启动睾丸下降。INSL3的作用失败直接或由于受体功能障碍导致隐睾（隐睾），这是最常见的先天性缺陷之一。在女性中，INSL3与卵泡选择有关。最近的证据表明，肽在调节男性和女性生殖细胞成熟中具有明确的作用。这些效应表明INSL3的激动剂和拮抗剂有潜力作为新型避孕方法或治疗不孕症的特异性药物。INSL3的作用是通过与g蛋白偶联受体LGR8相互作用介导的。这种受体在睾丸和卵巢以及包括大脑在内的其他组织中表达。然而，人们对INSL3如何与LGR8相互作用产生生理反应知之甚少。因此，我们将确定负责受体结合的肽的结构特征。这将通过使用化学肽合成不仅是INSL3，而且肽的类似物，包含修饰残基或结构域实现。这些将被用于分析INSL3的特征活性，并将结果与现代生物分子相互作用分析获得的结果一起用于确定INSL3的受体结合区域。这些信息，连同利用核磁共振波谱法确定INSL3的三维结构，然后将利用计算机辅助分子模型来设计更小、更稳定、口服活性的类似物来传播。这种缩小尺寸的模拟物相应地更便宜，更容易制备和处理，将在人类生育的治疗调节方面具有巨大的潜力。

Insulin-like peptide 3 (INSL3) is a peptide hormone that is structurally similar to insulin. It is produced in both the testes and the ovaries. In the male, one of its primary roles is to initiate testes descent during fetal development via a direct action on the gubernaculum ligament. Failure of INSL3 action either directly or due to receptor malfunction causes cryptorchidism (undescended testes), one of the most common congenital defects. In the female, INSL3 is implicated in follicle selection. More recent evidence shows that the peptide has clear roles in modulating male and female germ cell maturation. These effects indicate that agonists and antagonists of INSL3 have potential as specific drugs for novel contraceptive approaches or infertility treatments in both sexes. The actions of INSL3 are mediated by interaction with a G-protein coupled receptor known as LGR8. This receptor is expressed in the testes and ovary as well as several other tissues including the brain. However, very little is known about how INSL3 interacts with LGR8 to produce its physiological responses. Consequently, we will determine the structural features of the peptide that are responsible for receptor binding. This will be achieved by use of chemical peptide synthesis of not only INSL3 but also of analogues of the peptide that contain modified residues or domains. These will be assayed for characteristic INSL3 activity and the results, together with those acquired by modern biomolecular interaction analyses, will be used to identify the receptor binding regions for INSL3. This information, together with a determination of the three-dimensional structure of INSL3 by using NMR spectroscopy, will then be disseminated using computer-assisted molecular modelling to design smaller, more stable, orally active analogues. Such mimetics of reduced size that are correspondingly cheaper and simpler to prepare and handle will have great potential for therapeutic regulators of human fertility.