I am interested in understanding the mechanism of action of two catalytic antibodies generated in the Scanlan lab. Our lab, in collaboration with the Fletterick lab (UCSF), determined the three-dimensional structure of a hydrolytic antibody termed 17E8. Modeling the structure of the active site suggested that the antibody employs a hydrolytic mechanism very similar to the class of enzymes known as serine proteases. We are now very close to having solved the structure of a second catalytic antibody, 29G11. Experimental results suggest that this antibody functions through a very different mechanism, despite its sequence similarity to 17E8. We hope that modeling of these two proteins will help explain some of the differences in activity. My project is to try to better understand the mechanism of these two antibodies by making site-directed mutations in their sequences. The ability to model the antibodies using the Computer Graphics Lab is key to choosing the important amino acids to mutate. In addition, I am able to examine the possible effects of an amino acid substitution before performing the actual experiment. Mutations of the active site, in particular, will help us to understand the mechanism of these antibodies and how individual residues contribute to either binding or catalytic activity. Modeling my structures in CGL helps me choose which are the critical amino acids to alter.
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