Structural biology of soft tick complement inhibitor (OMCI) alone and in complex with C5

软蜱补体抑制剂 (OMCI) 单独和与 C5 复合的结构生物学

• 批准号: BB/D003628/1
• 负责人: Susan Lea
• 金额: $ 33.7万
• 依托单位: University of Oxford
• 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%2FD003628%2F1
• 关键词: Structural; biology; soft; tick; complement

The complement system is a group of approx. 30 proteins that act together to form a frontline defence against invasion by parasites and other pathogens. As for all proteins we can only really understand the ways in which these proteins act to combat invasion by knowledge of their detailed, atomic, structure. However, many of the complement system proteins are difficult to study at this level of detail and we therefore have little atomic level structural information for the central components of this important biological system. Most parasites attempt to overcome the defence mounted by the complement system by expressing molecules that act specifically to interfere with these defences. This application seeks to use an anti-complement molecule expressed by a tick to increase our understanding both of how the tick protein works (by solving the atomic structure of this inhibitor) and also to increase our understanding of one of the key complement components, a protein called C5, by discovering precisely how the tick inhibitors prevent its correct functioning. A vital first step towards this aim is the identification of the site of interaction between C5 and the inhibitor. We will use a variety of different biochemical methods to identify the site of interaction. Including (1) determining which fragments of C5 bind to the inhibitor, (2) studying the interaction between C5 and inhibitor in competition with complement components which bind to C5, and (3) introducing single amino acid changes to C5 that prevent the inhibitor binding. Armed with these data and materials (purified fragments of C5) we will attempt to determine an atomic structure for a complex between C5 (or a significant part of it) and the tick inhibitor to give us a framework on which to interpret our biochemical data and prior knowledge of the biological function of C5.

补体系统是一组近似的。30种蛋白质共同作用，形成抵御寄生虫和其他病原体入侵的前线防御。至于所有的蛋白质，我们只能通过了解它们的详细原子结构来真正了解这些蛋白质对抗入侵的方式。然而，许多补体系统蛋白质很难在这个细节水平上进行研究，因此我们对这个重要生物系统的核心组成部分几乎没有原子水平的结构信息。大多数寄生虫试图通过表达特异性干扰补体系统防御的分子来克服这些防御。本申请旨在使用蜱表达的抗补体分子来增加我们对蜱蛋白如何工作的理解（通过解决这种抑制剂的原子结构），并通过精确发现蜱抑制剂如何阻止其正确发挥功能来增加我们对关键补体成分之一（称为C5的蛋白质）的理解。实现这一目标的重要第一步是确定C5和抑制剂之间的相互作用位点。我们将使用各种不同的生物化学方法来确定相互作用的位点。包括（1）确定C5的哪些片段与抑制剂结合，（2）研究C5与抑制剂之间的相互作用，以与结合C5的补体组分竞争，和（3）向C5引入阻止抑制剂结合的单个氨基酸变化。有了这些数据和材料（C5的纯化片段），我们将尝试确定C5（或其重要部分）和蜱抑制剂之间复合物的原子结构，为我们提供一个框架，以解释我们的生化数据和C5生物学功能的先验知识。