CRYSTAL-STRUCTURE OF A CATALYTIC ANTIBODY FAB WITH ESTERASE-LIKE ACTIVITY

Background: Antibodies with catalytic properties can be prepared by el iciting an antibody response against 'transition state analog' haptens . The specificity, rate and number of reaction cycles observed with th ese antibodies more closely resemble the properties of enzymes than an y of the many other known enzyme-mimicking systems. Results: We have d etermined to 3 angstrom resolution the first X-ray structure of a cata lytic antibody Fab. This antibody catalyzes the hydrolysis of a p-nitr ophenyl ester. In conjunction with binding studies in solution, this s tructure of the uncomplexed site suggests a model for transition state fixation where two tyrosines mimic the oxyanion binding hole of serin e proteases. A comparison with the structures of known Fabs specific f or low molecular weight haptens reveals that this catalytic antibody h as an unusually long groove at its combining site. Conclusion: Since t ransition state analogs contain elements of the desired product, produ ct inhibition is a severe problem in antibody catalysis. The observati on of a long groove at the combining site may relate to the ability of this catalytic antibody to achieve multiple cycles of reaction.