Structural biology of antibody:antigen complexes

抗体的结构生物学：抗原复合物

• 批准号: 8516984
• 负责人: STEPHEN COPLAN HARRISON
• 金额: $ 37.29万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516984
• 关键词: Affinity; Antibodies; Antigen-Antibody Complex; Antigens; B cell repertoire; Binding; Characteristics; Complex; Cryoelectron Microscopy; Epitopes; Exposure to; Foundations; Goals; Immune response; Immunization; Infection; Instruction; Knowledge; Link; Methods; Resolution; Structure; Technology; Vaccination; Vaccines; Virus; Work; base; design; influenzavirus; reconstruction; response; structural biology; vaccine development

The overall goals of Project 3 are to understand the high-resolution structural correlates of immunodominance and to provide structural foundations for designing immunogens that can focus an immune response on particular, chosen epitopes. Our principal hypothesis is that structural contributions to immunodominance can be revealed by correlating structures of antibody-antigen complexes with knowledge of the repertoire from which the antibody was derived and reconstruction of the mutational sequence that led to the affinity matured antibody from its germline precursor. The high-throughput approaches described in Project 1 can give us the required information about repertoire and about affinity maturation of antibodies denved from the settings of vaccination vs. infection. We propose here to provide the corresponding three-dimensional information. We have the following four Aims. [1) What are the structural characteristics of cross-reactive antibodies bound with their HA epitopes? We will determine structures of selected representatives of the antibodies studied in projects 1 and 2, in complex with the relevant influenza virus HA. We will begin with standard crystallographic approaches, but proceed as rapidly as possible to higher-throughput cryoEM methods (Aim 2; see also Core C). (2) We will develop approaches for mounting

项目 3 的总体目标是了解免疫优势的高分辨率结构相关性 并为设计免疫原提供结构基础，使免疫反应集中于 特别的、选定的表位。我们的主要假设是，结构对免疫优势的贡献可以 通过将抗体-抗原复合物的结构与来自的库的知识相关联来揭示 抗体的来源和导致亲和力成熟的突变序列的重建 来自其种系前体的抗体。项目 1 中描述的高通量方法可以为我们提供 所需的有关抗体库和有关从设置中衍生的抗体亲和力成熟的信息 疫苗接种与感染。我们这里建议提供相应的三维信息。我们 有以下四个目标。 [1) 结合的交叉反应抗体的结构特征是什么？ 他们的HA表位？我们将确定项目中研究的抗体的选定代表的结构 1和2，与相关流感病毒HA复合。我们将从标准晶体学开始 方法，但尽快转向更高通量的冷冻电镜方法（目标 2；另请参阅核心 C）。 (2)我们将开发安装方法