MEASLES VIRUS AND ITS CELLULAR RECEPTOR CD46

麻疹病毒及其细胞受体CD46

• 批准号: 6619858
• 负责人: THILO STEHLE
• 金额: $ 24.43万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6619858
• 关键词: CD antigens; X ray crystallography; antiviral antibody; epitope mapping; measles virus; microorganism hemagglutinin; polymerase chain reaction; protein structure function; receptor binding; receptor expression; site directed mutagenesis; tissue /cell culture; virus antigen; virus receptors

The goal of this proposal is to understand the interactions between measles virus and its cellular receptor in order to provide a basis for the design of anti-viral drugs. Despite an available vaccine, measles remains one of the major causes of child death worldwide, and our work will guide efforts to find new ways to control this pathogen. We will determine the three- dimensional structures of measles virus hemagglutinin and of human CD46, a measles virus receptor. The physiological role for CD46 is as a cofactor that accelerates the deactivation of the third and fourth complement components, thereby protecting host cells from complement-dependent attack. It appears that measles virus and the physiological ligands for CD46 bind to discrete parts of the molecule. Specifically, the extracellular portion of CD46 consists of four short consensus repeats (SCRs) that contain binding sites for the measles virus hemagglutinin (in SCR1-SCR2) and complement regulatory activity (in SCR2-SCR4). One can therefore envisage the discovery of selective anti-viral inhibitors. The experiments described in Specific Aim 1 concern the expression, crystallization and X-ray structure determination of several two-domain CD46 fragments as well as a fragment that comprises all four SCRs. Since the molecule probably has some interdomain flexibility, studying the two-domain fragments increases the likelihood of obtaining crystals that can diffract to molecular resolution. Crystals for the SCR1-SCR2 fragment have already been produced, and the structure determination of this fragment has been achieved. In Specific Aim 2, we will use this structural information as a guide to carry out site-directed mutagenesis experiments and measles virus binding studies that will probe the interactions with the virus in more detail. In parallel, we will express and crystallize a soluble form of the measles virus hemagglutinin protein that contains the CD46 binding site, and we will determine its crystal structure as part of Aim 2. These structural studies are a necessary antecedent for rational drug design against measles virus. They are also likely to provide insights into strategies for vaccine and drug design against paramyxoviruses such as respiratory syncytial virus in general.

本课题旨在了解麻疹病毒与其细胞受体之间的相互作用，为抗病毒药物的设计提供依据。尽管有可用的疫苗，但麻疹仍然是全世界儿童死亡的主要原因之一，我们的工作将指导寻找控制这种病原体的新方法的努力。我们将确定麻疹病毒血凝素和人CD46（麻疹病毒受体）的三维结构。CD46的生理作用是作为辅助因子加速第三和第四补体成分的失活，从而保护宿主细胞免受补体依赖性攻击。麻疹病毒和CD46的生理配体似乎结合到分子的离散部分。具体来说，CD46的细胞外部分由四个短一致重复序列（SCRs）组成，包含麻疹病毒血凝素（在SCR1-SCR2中）和补体调节活性（在SCR2-SCR4中）的结合位点。因此，人们可以设想选择性抗病毒抑制剂的发现。具体目标1中描述的实验涉及几个双域CD46片段以及包含所有四个scr的片段的表达，结晶和x射线结构测定。由于分子可能具有一定的域间灵活性，研究双域片段增加了获得可以衍射到分子分辨率的晶体的可能性。已经制备出了SCR1-SCR2片段的晶体，并实现了该片段的结构测定。在Specific Aim 2中，我们将使用这些结构信息作为指导，开展定点诱变实验和麻疹病毒结合研究，更详细地探索与病毒的相互作用。同时，我们将表达和结晶一种含有CD46结合位点的麻疹病毒血凝素蛋白的可溶性形式，我们将确定其晶体结构作为Aim 2的一部分。这些结构研究为合理设计抗麻疹病毒药物提供了必要的前提。它们还可能为针对副粘病毒（如呼吸道合胞病毒）的疫苗和药物设计策略提供见解。

项目成果

Crystallization and preliminary crystallographic analysis of the measles virus hemagglutinin in complex with the CD46 receptor.

麻疹病毒血凝素与 CD46 受体复合物的结晶和初步晶体学分析。

• DOI: 10.1107/s1744309109050593
• 发表时间: 2010
• 期刊: Acta crystallographica. Section F, Structural biology and crystallization communications
• 作者: Santiago,César;Gutiérrez-Rodríguez,Angel;Tucker,PaulA;Stehle,Thilo;Casasnovas,JoséM
• 通讯作者: Casasnovas,JoséM

Structural evidence for common functions and ancestry of the reovirus and adenovirus attachment proteins.

呼肠孤病毒和腺病毒附着蛋白的共同功能和祖先的结构证据。

• DOI: 10.1002/rmv.379
• 发表时间: 2003
• 期刊: Reviews in medical virology
• 影响因子: 11.1
• 作者: Stehle,Thilo;Dermody,TerenceS
• 通讯作者: Dermody,TerenceS

Structural similarities in the cellular receptors used by adenovirus and reovirus.

腺病毒和呼肠孤病毒使用的细胞受体的结构相似。

• DOI: 10.1089/0882824041310621
• 发表时间: 2004
• 期刊: Viral immunology
• 影响因子: 2.2
• 作者: Stehle,Thilo;Dermody,TerenceS
• 通讯作者: Dermody,TerenceS

Structure of the extracellular portion of CD46 provides insights into its interactions with complement proteins and pathogens.

• DOI: 10.1371/journal.ppat.1001122
• 发表时间: 2010-09-30
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Persson BD;Schmitz NB;Santiago C;Zocher G;Larvie M;Scheu U;Casasnovas JM;Stehle T
• 通讯作者: Stehle T

A molecular dynamics study of reovirus attachment protein sigma1 reveals conformational changes in sigma1 structure.

呼肠孤病毒附着蛋白 sigma1 的分子动力学研究揭示了 sigma1 结构的构象变化。

• DOI: 10.1529/biophysj.103.030825
• 发表时间: 2004
• 期刊: Biophysical journal
• 影响因子: 3.4
• 作者: Cavalli,Andrea;Prota,AndreaE;Stehle,Thilo;Dermody,TerenceS;Recanatini,Maurizio;Folkers,Gerd;Scapozza,Leonardo
• 通讯作者: Scapozza,Leonardo