Structural insights into antibody catalysis are critical for novel design and improvement of effective biocatalysts. Thus, a major goal in this renewal is to focus on catalytic antibodies that will have either a direct impact on public health issues, be of general chemical and biotechnological utility, or will provide mechanistic guidelines for enhancement of catalytic efficiency or specificity. Structural, biochemical, chemical, and theoretical approaches will be combined in order to provide directions for new ligand design or mutagenesis. The antibodies under study catalyze pericyclic, elimination, transfer and esterase reactions. General principles derived from these abzyme crystal structures will be specifically applied to enhance the cocaine binding and degrading activities of humanized antibodies and human enzymes. Cocaine-degrading antibodies have tremendous therapeutic potential in immunotherapy for cocaine addiction, thereby reducing the social and economic burden caused by this drug. The individual specific aims are to determine x-ray crystal structures of abzymes that catalyze important classes of chemical reactions, cocaine-binding antibodies, and cocaine esterases in an iterative cycle of structure determination, redesign of ligands, and mutagenesis. The progress of these projects is in various stages, from purified proteins, to crystallized proteins, to structures in refinement, consistent with a productive five-year plan. Given that catalytic antibodies have now been produced that are as efficient as natural enzymes, the next goal is to make further progress in increasing the efficiency and specificity of enzymes of biomedical, biotechnological, and chemical importance. In this way, the enormous potential power of the immune system can be harnessed to rapidly develop tailor-made catalysts in a few weeks, compared to the billions of years it has taken for evolution of natural enzymes.
| Debler, Erik W; Müller, Roger; Hilvert, Donald et al. (2009) An aspartate and a water molecule mediate efficient acid-base catalysis in a tailored antibody pocket. Proc Natl Acad Sci U S A 106:18539-44 |
| Debler, Erik W; Kaufmann, Gunnar F; Kirchdoerfer, Robert N et al. (2007) Crystal structures of a quorum-quenching antibody. J Mol Biol 368:1392-402 |
