CRYSTAL STRUCTURES OF ANTIBODIES AND IDIOTYPIC CASCADE

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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.