My laboratory focuses on three major projects.
We are studying the cysteine proteinases from HAV, rhinovirus 2 and the coronavirus of SARS. We have characterized several new inhibitors of these cysteine proteinases and are working hard to crystallize the fusion protein 3CD from HRV2 with the view to understand its cleavage specificity. We also work on the structure of NS5B, the RNA dependent RNA polymerase from hepatitis C virus (HCV). In collaboration with ViroChem Pharma Inc., we have determined the structures of ~60 Non-Nucleoside Inhibitors bound to NS5B. The structures of a new crystal form of NS5B in complex with several nucleotides have suggested how this enzyme functions.
We are making great progress in understanding lysine biosynthesis in plants. Both involve structures of enzymes derived from Arabidopsis thaliana, DAP aminotransferase and DAP epimerase. The former is an enzyme also found in Chlamidia and we are working on the structure of this enzyme as well.
We have made progress in our study of potential drug targets in Mycobacterium tuberculosis (Mtb). Our work on the enzymes and proteins involved in arginine biosynthesis in Mtb is progressing well. We have determined the structures of the ornithine transcarbamylase, the sixth enzyme in this pathway and we have crystals of ArgH, an argininosuccinate lyase from Mtb. ArgH catalyzes the final step of arginine biosynthesis. We are also targeting the enzymes involved in peptidoglycan biosynthesis and have recently solved the structure of UDP-N-acetylglucosamine phosphorylase (GlmU). The structure of MetZ, O-succinylhomoserine sulfhydrolase, an enzyme from Mtb involved in methionine biosynthesis has been solved and we are working to understand the mechanism. In collaboration with a group in UC Davis we have discovered two nanomolar inhibitors of an epoxide hydrolase from Mtb.
We have obtained crystals of an ScFv that recognizes an epitope on the prion protein.