CATALYTIC ANTIBODY STRUCTURES - AN EARLY ASSESSMENT

The three-dimensional structures of four catalytic antibodies, three o f which were complexed with transition-state analogs, have been determ ined by X-ray crystallographic methods. An additional catalytic antibo dy structure has been deduced using homology modeling methods, and the information derived from the resulting model has been the basis for s ite-directed mutagenesis experiments. Analysis of these crystal struct ures suggests that the primary source of catalytic activity in three o f the antibodies is primarily shape and charge complementarity between the combining sites and the transition-state-analog haptens. The four th structure may contain a modified ''catalytic triad,'' with histidin e, serine, and tyrosine side chains positioned so that they could part icipate in the chemical transformation. Otherwise, the abzyme structur es are representative of antibody structures in general, and do not po ssess any particularly unusual features that would suggest a classific ation outside the normal range of variation expected within the immuno globulin family. Rather, the catalytic activity of these antibodies ca n be explained entirely on the basis of the local arrangement of resid ues that line the binding sites for their haptenic antigens. In additi on, the structures provide strong evidence that the conserved immunogl obulin framework can provide a highly suitable context to serve as the basis for a generalized, programmable catalyst.