STRUCTURAL STUDIES OF CATALYTIC ANTIBODIES. A. Heine, E. A. Stura, K. D. Janda, C. F. Barbas III, R. A. Lerner, I. A. Wilson, The Scripps Research Institute, Department of Molecular Biology, 10666 North Torrey Pines Road, La Jolla, CA 92037.

The diversity of the immune system can be exploited to generate catalytic antibodies, which not only catalyze a wide variety of reactions similiar to enzymes, but also otherwise disfavored or difficult reactions. The structures of catalytic antibodies and their corresponding complexes with transition state analoges or substrates are essential to understand the antibody-antigen interaction and the mechanism involved in catalysis. A comparison of such mechanisms with those of corresponding enzymes might give indications for different rate enhancements. By knowing which residues in the active site are involved in catalysis, site directed mutagenesis can be done to improve the catalytic rate.

The aldolase antibody 38C2 mimics the natural class I aldolase enzyme. A similiar mechanism for catalysis is proposed. The [[epsilon]]-amino group of a lysine residue in the active site forms an enamine with a ketone substrate, activating it as an aldol donor. Crystals diffract to at least 3.2 Å and a dataset was collected to that resolution. Subsequently studied antibodies include the anti-metallocene antibody 13G5, which catalyzes a Diels-Alder reaction. A ferrocene derivative was used as the haptenic group. Data were collected to 2.7 Å for the Fab and to 2.8 Å for the isomorphous complex. A syn elimination of an acyclic substrate is catalyzed by antibody 1D4. In the absence of the catalytic antibody this disfavored reaction does not occur. Crystallization conditions, structure solution and progress in refinement will be reported.