CRYSTAL STRUCTURES OF ANTIBODIES AND IDIOTYPIC CASCADE

说明(改编自《调查员摘要》)：建议 探讨抗体/抗原识别的分子机制。 两种相关抗鸡蛋蛋白的X射线晶体结构测定 溶菌酶(HEL)抗体D44.1和F10.6.6，表现出显著的 对抗原亲和力的差异。FV的结构 这两个抗体的片段将详细说明分子间 相互作用，稳定抗体抗原复合体，形成 抗体对抗原的分子识别。分析了两个这样的问题 密切相关的抗体可以帮助理解分子 微调的亲和成熟反应的基础。它更远了 建议通过以下方式剖析独特型网络的结构基础 两种抗独特型和抗独特型药物的晶体结构分析 抗体AF14和AF52。这些抗-抗-ID的结构 抗体，结合先前对病毒结构的分析 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。完整的 披露这种独特型级联将极大地帮助应用程序 抗id抗体，模拟抗原，用作免疫化学和 药理制剂。分子模仿是一种普遍存在的现象 生物学，是许多药学活动的基础 有用的化合物，如管库仑和多环阿片类药物。 抗体为研究分子模仿提供了一个强有力的工具，因为 某些抗独特型抗体已被证明在功能上模仿 抗原。HEL(抗原)-D1.3(抗体)-E5.2(抗id)-AF14、AF52 (反身份证)系统将提供这样的工具。最后，提出了一种新的研究思路。 用X射线结晶学方法研究大分子组装 以及这种结构与其催化机制的关系 一种鲁马津合成酶，核黄素生产中的关键酶，从 布鲁氏菌。细菌缺乏一种摄取系统 核黄素。因此，它们依赖于 这种辅酶应该很容易受到核黄素抑制剂的影响 综合。由于卢马津合成酶在哺乳动物中不存在，因此 对其三维结构的了解可以作为 具有治疗活性的酶抑制剂的合理设计。

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.