MOLECULAR RECOGNITION AND MECHANISM DISPLAYED BY CATALYTIC ANTIBODIES

Although numerous of strategies for the generation of catalytic antibodies have been developed, investigations of the expressed immunoglobulin proteins have resulted in only a limited understanding of antigen-combining site structures and catalytic function. When mice are immunized with a hapten conjugated to a carrier protein, a few, and occasionally several, of the dozens of antibodies that bind the hapten are characterized to be catalytic. Thus, the diversity of the immune response can provide a panel of catalytic antibodies that possess varying degrees of catalytic activity and substrate specificity. However, it is unclear how structural differences in the antigen-combining sites of these antibodies correlate with catalytic activity. For example, how do catalytic and noncatalytic (affinity) antibodies differ on a structural basis? Are catalytic antibodies derived from noncatalytic antibodies by mechanisms involved in antibody diversification or are they encoded in the germ-line repertoire? To understand the structure-function relationship and the molecular mechanisms by which catalytic antibodies are generated in immune responses, heavy and light chain variable region primary structures of antibody repertoires (involving catalytic and noncatalytic antibodies) were deduced from cDNA generation, cloning, and sequencing, in addition, three-dimensional molecular models were constructed based on the primary sequence data and kinetic studies using a variety of substrate derivatives.