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Our research interest is to study the structure-function relationship of biologically interesting molecules by using X-ray diffraction methods, one of the most powerful techniques to date to study macromolecular structure. Currently our studies are focused on the following projects:
Ribbon structure of the MCAD tetramer complexed with C8-CoA
Acyl-CoA Dehydrogenases and Related Enzymes
Acyl-CoA Dehydrogenases are a family of enzymes that are involved in both the first oxidative step in the metabolism of fatty acids and in the catabolism of some amino acids. Electron transfer from the primary dehydrogenase to the main mitochondrial respiratory chain is catalyzed, in sequence, by electron transfer flavoprotein (ETF) and the membrane-associated ETF-ubiquinone oxidoreductase (ETF-QO). The crystal structures of several acyl-CoA dehydrogenases including medium chain acyl-CoA dehydrogenase, short chain acyl-CoA dehydrogenase, and isovaleryl-CoA dehydrogenase have been determined in our laboratory. These structures reveal their catalytic mechanism as well as the structural basis for the substrate specificity. Currently we are extending these studies to site-specific mutants, inhibitor/substrate complexes, and to other members of the dehydrogenase family.
We have recently obtained high resolution structures of human ETF and a bacterial ETF. These, together with those of various acyl-CoA dehydrogenases, have enabled us to study the molecular basis of electron transfer between the dehydrogenases and ETF and of flavoprotein-flavoprotein interactions, in general. We have recently crystallized the membrane associated protein, ETF-QO and its complete structure determination is in progress.
Ribbon diagram of NADPH-Cytochrome P450 oxidoreductase
NADPH-Cytochrome P450 oxidoreductase
NADPH-Cytochrome P450 Reductase exists in every tissue in which cytochrome P450-mediated reactions occur of both endogenous substrates, including steroids, fatty acids, and prostaglandins, and exogenous compounds such as therapeutic drugs, environmental toxicants, and carcinogens. We have recently solved the three dimensional structure of the rat liver reductase. The structure shows how the two flavins (FMN and FAD) are communicating with each other and provides insights into not only the interaction of the reductase with its physiological electron partner, cytochrome P450, but also the mechanism of electron transfer and its regulation in other FMN- and FAD-containing enzymes, including nitric oxide synthase isozymes. We are extending our studies to interactions between cytochromes P450 and the reductase, as well as to other related enzymes.
NADPH-cytochrome P450 reductase dancing with cytochrome P450 Movie
Structure/Function studies of Mannose 6-Phosphate Receptors (MPRs)
MPRs are responsible for the targeting of lysosomal acid hydrolases to lysosomes. In collaboration with Dr. Nancy Dahms, we have been studying the structure/function relationships of these receptors. We have solved the structures of the cation dependent MPR (CD-MPR) with and without mannose 6-phosphate ligand and complexes with high mannose oligosaccharides. Currently, we are extending our studies to the larger of the two receptors, the insulin-like growth factor II/cation-independent MPR (IGF-II/CI-MPR).