CRYSTAL STRUCTURES OF ANTIBODIES AND IDIOTYPIC CASCADE

抗体的晶体结构和独特型级联

• 批准号: 2806551
• 负责人: BRADFORD C BRADEN
• 金额: $ 9.27万
• 依托单位: BOWIE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2806551
• 关键词: Brucellaceae; X ray crystallography; antigen antibody reaction; antiidiotype antibody; bacterial proteins; enzyme mechanism; enzymes; lysozyme; molecular assembly /self assembly; protein structure; structural biology

DESCRIPTION (Adapted from the Investigator's Abstract): It is proposed to investigate the mechanism of antibody/antigen recognition by determining the X-ray crystal structures of two related anti-hen egg lysozyme (HEL) antibodies, D44.1 and F10.6.6, that exhibit remarkable differences in affinity for the antigen. The structures of the Fv fragments of these two antibodies will detail the intermolecular interactions, which stabilize the antibody antigen complex and form the molecular recognition of antibody for antigen. Analysis of two such closely related antibodies can serve the understanding of the molecular basis of the fine-tuned affinity maturation response. It is further proposed to dissect the structural basis of idiotypic networks by analyzing the crystal structures of two anti-anti-idiotypic and antibodies, AF14 and AF52. The structures of these anti-anti-Id antibodies, in concert with the prior analysis of the structures of the antigen (HEL), antibody (D1.3) and anti-id antibody (E5.2), will provide the first detailed molecular mechanism of idiotypic networks. The full disclosure of this idiotypic cascade will greatly aid in the application of anti-id antibodies, mimicking antigens, for use as immunochemical and pharmacological agents. Molecular mimicry is a widespread phenomenon in biology and is the basis for the activity of many pharmaceutically useful compounds such as tubocurare and the polycyclic opiods. Antibodies offer a powerful tool for studying molecular mimicry since certain anti-idiotypic antibodies have been shown to functionally mimic antigens. The HEL (antigen)-D1.3 (antibody)-E5.2 (anti-id)-AF14,AF52 (anti-anti-Ids) system will offer such a tool. Finally, it is proposed to study, by X-ray crystallographic methods, the macromolecular assembly and the relationship of that structure to the mechanism of catalysis of a lumazine synthase, a key enzyme in the production of riboflavin, from Brucella bacterium. Bacteria are devoid of an uptake system for riboflavin. They are therefore dependent of the internal synthesis of this co-enzyme and should be vulnerable to inhibitors of riboflavin synthesis. Since lumazine synthase is not present in mammals, the knowledge of its three-dimensional structure could serve as a basis for the rational design of enzymatic inhibitors with therapeutic activity.

描述（改编自研究者摘要）：拟定 研究抗体/抗原识别的机制， 测定了两种相关抗鸡蛋的X射线晶体结构 溶菌酶（HEL）抗体D44.1和F10.6.6，表现出显著的 对抗原的亲和力的差异。Fv的结构 这两种抗体的片段将详细说明分子间 相互作用，其稳定抗体抗原复合物并形成 抗体对抗原的分子识别。分析两个这样的 密切相关的抗体可以帮助理解分子 基于微调的亲和力成熟反应。进一步 建议解剖独特型网络的结构基础， 分析了两种抗-抗-独特型和 抗体，AF 14和AF 52。这些抗-抗-Id的结构 抗体，与先前对抗体结构的分析一致， 抗原（HEL）、抗体（D1.3）和抗id抗体（E5.2）将提供 独特型网络的第一个详细的分子机制。充分 这种独特型级联反应的公开将极大地有助于 模拟抗原的抗ID抗体，用作免疫化学和 药理学试剂。分子拟态是一种广泛存在的现象， 生物学，是许多药物活性的基础 有用的化合物如筒箭毒和多环阿片类。 抗体为研究分子模拟提供了强有力的工具， 某些抗独特型抗体已经显示出功能上模拟 抗原HEL（抗原）-D1.3（抗体）-E5.2（抗id）-AF 14、AF 52 （抗-抗-Ids）系统将提供这样的工具。最后提出 通过X射线晶体学方法研究大分子组装， 以及这种结构与催化机制的关系， 一种乌马嗪合酶，一种生产核黄素的关键酶， 布鲁氏杆菌。细菌缺乏摄取系统， 核黄素因此，它们依赖于 这种辅酶，应该是容易受到核黄素抑制剂 合成.由于鲁马嗪合酶不存在于哺乳动物中， 其三维结构的知识可以作为基础， 合理设计具有治疗活性的酶抑制剂。

项目成果

Structural, functional and immunological studies on a polymeric bacterial protein.

聚合细菌蛋白的结构、功能和免疫学研究。

• DOI: 10.1590/s0100-879x2000000700003
• 发表时间: 2000
• 期刊: Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas
• 作者: Baldi,PC;Velikovsky,CA;Braden,BC;Giambartolomei,GH;Fossati,CA;Goldbaum,FA
• 通讯作者: Goldbaum,FA