Ph.D. Molecular Biophysics,
Oxford University, England, 1978
Molecular Genetics and Biochemistry Research Group
Neurobiology and Behavior Research Group
Molecular Genetics/Cell Physiology
Crystallography and Bioinformatics Neurobiology & Molecular Genetics
The major research theme of my laboratory is to understand the molecular basis of disease and help to develop new treatment strategies. We study key regulatory proteins at the molecular level by applying the techniques of bioinformatics, biochemistry and crystallography to study the structure and function of protein-ligand complexes. Current research projects include:
1. Studies of drug resistance in HIV and comparative studies of other retroviruses. HIV and other retroviruses cause AIDS and cancer in humans and other animals. We are studying the crystal structures and enzymatic activities of drug resistant mutants of HIV proteases in order to understand the molecular basis for drug resistance. New protease inhibitors are studied as potential drug candidates to overcome resistance. Comparative studies on structure and substrate specificity are being performed on related proteases from Rous sarcoma virus and HTLV.
2. The Tcl1 family of proteins involved in chronic lymphocytic leukemias. We have determined the crystal structures of two members of the Tcl1 family of oncoproteins. These proteins fold into an eight-stranded beta barrel of unique topology. However, their role in lymphoid cell biology is not clear.
3. Bacterial carboxylesterases. We are studying the structures and activities of carboxylesterases from Geobacillus stearothermophilus . These enzymes are members of the serine hydrolase family and are related to physiologically important human enzymes. The crystal structure of Est30 showed a reaction intermediate and has provided insights into the reaction mechanism of this important family of enzymes.
4. Human glucokinase and mutations involved in type II diabetes. We have built models to understand how glucokinase binds to its two substrates, glucose and ATP. These glucokinase models have proved invaluable for understand the effects of glucokinase mutations involved in development of Mature Onset Diabetes of the Young.