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， 特定的，选择的表位我们的主要假设是，免疫优势的结构贡献， 通过将抗体-抗原复合物的结构与来自抗体-抗原复合物的库的知识相关联， 抗体的来源和导致亲和力成熟的突变序列的重建 抗体从其生殖系前体。项目1中描述的高通量方法可以为我们提供 所需的关于库的信息和关于抗体的亲和力成熟的信息， 疫苗接种与感染我们建议在这里提供相应的三维信息。我们 有以下四个目标。[1)结合的交叉反应性抗体的结构特征是什么 他们的HA抗原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。我们将开始从标准晶体学 方法，但尽可能快地进行更高通量的cryoEM方法（目标2;另见核心C）。 (2)我们将开发安装方法，