ROUTES TO CATALYSIS - STRUCTURE OF A CATALYTIC ANTIBODY AND COMPARISON WITH ITS NATURAL COUNTERPART

The three-dimensional structure of a catalytic antibody (1F7) with cho rismate mutase activity has been determined to 3.0 angstrom resolution as a complex with a transition state analog. The structural data sugg est that the antibody stabilizes the same conformationally restricted pericyclic transition state as occurs in the uncatalyzed reaction. Ove rall shape and charge complementarity between the combining site and t he transition state analog dictate preferential binding of the correct substrate enantiomer in a conformation appropriate for reaction. Comp arison with the structure of a chorismate mutase enzyme indicates an o verall similarity between the catalytic mechanism employed by the two proteins. Differences in the number of specific interactions available for restricting the rotational degrees of freedom in the transition s tate, and the lack of multiple electrostatic interactions that might s tabilize charge separation in this highly polarized metastable species , are likely to account for the observed 10(4) times lower activity of the antibody relative to that of the natural enzymes that catalyze th is reaction. The structure of the 1F7 Fab'-hapten complex provides con firmation that the properties of an antibody catalyst faithfully refle ct the design of the transition state analog.