Catalytic Antibody Structures: An Early Assessment

The three‐dimensional structures of four catalytic antibodies, three of which were complexed with transition‐state analogs, have been determined by X‐ray crystallographic methods. An additional catalytic antibody structure has been deduced using homology modeling methods, and the information derived from the resulting model has been the basis for site‐directed mutagenesis experiments. Analysis of these crystal structures suggests that the primary source of catalytic activity in three of the antibodies is primarily shape and charge complementarity between the combining sites and the transition‐state‐analog haptens. The fourth structure may contain a modified “catalytic triad,” with histidine, serine, and tyrosine side chains positioned so that they could participate in the chemical transformation. Otherwise, the abzyme structures are representative of antibody structures in general, and do not possess any particularly unusual features that would suggest a classification outside the normal range of variation expected within the immunoglobulin family. Rather, the catalytic activity of these antibodies can be explained entirely on the basis of the local arrangement of residues that line the binding sites for their haptenic antigens. In addition, the structures provide strong evidence that the conserved immunoglobulin framework can provide a highly suitable context to serve as the basis for a generalized, programmable catalyst.