The structure and function of the human respiratory syncytial virus M2-1 protein and its critical interaction with viral cofactors

人呼吸道合胞病毒M2-1蛋白的结构和功能及其与病毒辅助因子的关键相互作用

• 批准号: MR/L007290/1
• 负责人: John Barr
• 金额: $ 59.88万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL007290%2F1
• 关键词: structure; function; human; respiratory; syncytial

Human respiratory syncytial virus (HRSV) is responsible for an extremely common respiratory disease, with most humans on earth being infected at least once before they reach the age of 2. In most adults, the disease is not life threatening. However, in the very young, the elderly and the immunocompromised, HRSV infections often require hospitalization and can be fatal. Recent studies suggest that each year HRSV is responsible for over 34 million lower respiratory tract infections and between 66,000 and 199,000 deaths. In addition, HRSV infection early in life may contribute towards increased incidence of asthma later in adulthood, which affects over 5 million people in the UK alone. There is no HRSV vaccine, and the only current option for preventing HRSV disease is to give vulnerable people repeated injections of a drug called palivizumab. However, this treatment is only moderately effective and is prohibitively expensive, therefore new treatments to combat HRSV disease are required. The experiments described in this proposal will identify several critical weaknesses in HRSV that will allow new drugs to be developed to prevent HRSV disease.HRSV is made of several different building blocks called proteins that must fit together very precisely in order to do their specific job. One of these building blocks is known as the M2-1 protein, and previous work has shown that it must interact with other pieces of the virus in order for HRSV to multiply. These interactions include: (1) interactions with the viral genetic material, (2) interactions with other copies of the M2-1 protein, and (3) interactions with another virus protein called P. The interactions occur because the shape of these individual components allows them to fit together very precisely, just like pieces of a very complicated jigsaw puzzle. The aim of this grant is to determine the shapes of the individual components in very high detail. By doing so, we will be able to design drugs that will interfere with the interaction and therefore prevent the virus from growing and causing disease.To do this work accurately, we will use a technique called X-ray crystallography, which will allow us to determine the precise shape of the N protein in three dimensions. This technique will reveal all the tiny clefts and crevices that allow these interactions, and critically, it will how us how this interaction could be blocked.

人类呼吸道合胞病毒（HRSV）是一种非常常见的呼吸道疾病，地球上大多数人在2岁之前至少感染过一次。在大多数成年人中，这种疾病不会危及生命。然而，在非常年轻，老年人和免疫功能低下，HRSV感染往往需要住院治疗，并可能是致命的。最近的研究表明，每年HRSV导致超过3400万例下呼吸道感染和66,000至199,000例死亡。此外，生命早期的HRSV感染可能导致成年后哮喘发病率增加，仅在英国就有超过500万人受到影响。没有HRSV疫苗，目前预防HRSV疾病的唯一选择是给脆弱的人重复注射一种名为帕利珠单抗的药物。然而，这种治疗仅是中等有效的，并且过于昂贵，因此需要新的治疗方法来对抗HRSV疾病。本提案中描述的实验将确定HRSV的几个关键弱点，这将允许开发新的药物来预防HRSV疾病。HRSV是由几种不同的称为蛋白质的构建模块组成的，这些蛋白质必须非常精确地组合在一起才能完成其特定的工作。其中一个构建模块被称为M2-1蛋白，以前的工作表明，它必须与病毒的其他片段相互作用，才能使HRSV繁殖。这些互动包括：（1）与病毒遗传物质的相互作用，（2）与M2-1蛋白的其他拷贝的相互作用，以及（3）与另一种称为P的病毒蛋白的相互作用。这些相互作用的发生是因为这些单个组件的形状允许它们非常精确地组合在一起，就像一个非常复杂的拼图游戏一样。该补助金的目的是非常详细地确定各个组件的形状。通过这样做，我们将能够设计出能够干扰这种相互作用的药物，从而防止病毒生长和引起疾病。为了准确地完成这项工作，我们将使用一种称为X射线晶体学的技术，这将使我们能够确定N蛋白在三维空间中的精确形状。这项技术将揭示所有允许这些相互作用的微小裂缝和裂缝，关键的是，它将告诉我们如何阻止这种相互作用。

项目成果

Virus Protein and Nucleoprotein Complexes

病毒蛋白和核蛋白复合物

• 发表时间: 2018
• 作者: Barr JN

The Structure of the Human Respiratory Syncytial Virus M2-1 Protein Bound to the Interaction Domain of the Phosphoprotein P Defines the Orientation of the Complex.

• DOI: 10.1128/mbio.01554-18
• 发表时间: 2018-11-13
• 期刊: mBio
• 影响因子: 6.4
• 作者: Selvaraj M;Yegambaram K;Todd EJAA;Richard CA;Dods RL;Pangratiou GM;Trinh CH;Moul SL;Murphy JC;Mankouri J;Éléouët JF;Barr JN;Edwards TA
• 通讯作者: Edwards TA