Structure and mechanism of a novel HIV assembly inhibitor

新型HIV组装抑制剂的结构和机制

• 批准号: BB/D005000/1
• 负责人: Joern Werner
• 金额: $ 30.2万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FD005000%2F1
• 关键词: Structure; mechanism; novel; HIV; assembly

In many cases the correct assembly of multiple proteins is critical for their biological function. By interfering specifically with certain protein-protein interactions one can control the assembly and as a result their function. The proteins that encapsulate the genetic information of the HIV virus undergo structural changes that change their arrangement from a spherical to a conical macromolecular assembly. The virus is only infections if the conical assembly is obtained. However, the protein-protein interactions that determine the spherical and the conical assemblies are not well understood. Several models for the arrangement have been proposed that are compatible with range of structural and biochemical data. We have a new small peptide that can interfere with both the spherical and conical assembly of the proteins in a yet unknown way. We are proposing to determine the interaction and the mechanism by which this peptide interferes with the formation of the assemblies. We intend to determine if the inhibitor simply blocks one or more important interfaces that are required for the assembly or whether it induces a conformational change or rearrangement in the protein such that assembly is disrupted. In addition we will determine the interaction of novel classes of molecules that have the same function. This will tell us if the mode of interaction of the inhibitor in hand is unique or if there are several solutions to the assembly inhibition. This will help us to understand the structural determinants that are required for the assembly and correct function of the HIV virus.

在许多情况下，多种蛋白质的正确组装对其生物学功能至关重要。通过特异性地干扰某些蛋白质与蛋白质之间的相互作用，人们可以控制它们的组装，从而控制它们的功能。包裹HIV病毒遗传信息的蛋白质经历结构变化，将其排列从球形变为圆锥形大分子组装。病毒只有在获得锥形装配体时才会感染。然而，决定球形和锥形组装的蛋白质-蛋白质相互作用尚未得到很好的理解。已经提出了几种与结构和生化数据相容的排列模型。我们有一种新的小肽，它可以以一种未知的方式干扰蛋白质的球形和锥形组装。我们建议确定相互作用和机制，这种肽干扰与组装的形成。我们打算确定抑制剂是否仅仅阻断组装所需的一个或多个重要界面，或者它是否诱导蛋白质的构象变化或重排，从而破坏组装。此外，我们将确定具有相同功能的新型分子之间的相互作用。这将告诉我们手中的抑制剂的相互作用模式是唯一的，还是有几种解决组装抑制的方法。这将有助于我们了解HIV病毒组装和正确功能所需的结构决定因素。