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

胰岛素样肽 3（胰岛素超家族的新成员）的结构功能和结构域最小化。

• 批准号: nhmrc : 350245
• 负责人: A/Pr Richard Hughes
• 金额: $ 19.2万
• 依托单位: The University of Melbourne
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2005
• 资助国家: 澳大利亚
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/structure-function-domain-insulin-superfamily/97759
• 关键词: Structure; function; domain; minimization; insulin

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.

胰岛素样肽3(INSL3)是一种结构类似于胰岛素的多肽激素。它是在睾丸和卵巢中产生的。在男性，它的主要作用之一是通过对引带韧带的直接作用，在胎儿发育过程中启动睾丸下降。INSL3作用的失败直接或由于受体功能障碍导致隐睾症(隐睾症)，这是最常见的先天性缺陷之一。在女性中，INSL3参与了卵泡的选择。最近的证据表明，该肽在调节男性和女性生殖细胞成熟方面具有明显的作用。这些效应表明，INSL3的激动剂和拮抗剂有可能作为新的避孕方法或不孕症治疗的特效药。INSL3的作用是通过与一种称为LGR8的G蛋白偶联受体相互作用来实现的。这种受体在睾丸和卵巢以及包括大脑在内的其他几个组织中都有表达。然而，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多肽的结构特征。这将不仅通过使用INSL3的化学多肽合成，而且通过使用含有修饰残基或结构域的多肽的类似物来实现。这些将被分析为特征的INSL3活性，结果将与现代生物分子相互作用分析获得的结果一起用于识别INSL3的受体结合区。这些信息，连同使用核磁共振光谱学确定的INSL3的三维结构，然后将使用计算机辅助分子模拟来传播，以设计更小、更稳定、口服活性的类似物。这种体积缩小的模拟物相应地更便宜，更容易准备和处理，将在治疗调节人类生育能力方面具有巨大的潜力。