Enzymes play central roles in all metabolic and cellular signaling pathways. Many investigators in the department are interested in understanding how enzymes function at the molecular and atomic level through a combination of modern biochemistry and structural biology. Techniques which are being employed to investigate enzyme structure and dynamics include X-ray crystallography, cryo-electron microscopy, NMR, mass spectroscopy and protein chemistry, while their chemical behavior is being characterized by rapid-reaction and steady-state kinetics, calorimetry, chemical analyses, and a variety of spectroscopies. Protein engineering is being used to study how structure determines function. Through the use of these techniques, investigators are able to probe mechanism and specificity in order to gain a greater understanding of how enzymes work and how they function in the context of molecular pathways in the cell. Such knowledge could provide the basis for new medical treatments, pollution-control strategies, or many other applications.
Structure and mechanisms of radical and redox-active enzymes, the chemical biology of B12 trafficking, regulation of human sulfur metabolism, biochemistry of B-vitamin associated human metabolic diseases, redox communication between glial, neural, dendritic and T cells in immune and neuro-immune function.
Structural biology and biophysics underlying microtubule-based intracellular transport.
Protein localization and vesicular transport in the eukaryotic secretory/endocytic pathways using budding yeast as a system and employing biochemical reconstitution, cell biology, genetics and fluorescence resonance energy transfer (FRET) microscopy as methods. Protein trafficking in human neurodegenerative and neurodevelopmental disease. Proteolytic processing by enzymes of the SPC/Kex2/furin family in yeast and metazoans with interest in structure-function relationships and discovery of human furin inhibitors as drug models for infectious, degenerative and neoplastic disease.
Structure and mechanism of coenzyme B12 and S-adenosylmethionine-dependent radical enzymes. Design and synthesis of "Teflon" proteins - introducing new properties into proteins using fluorinated amino acids.
Biochemical, biophysical, and structural approaches to understanding mechanisms of human DNA repair.
Mechanistic enzymology with a focus on flavoproteins involved in pyrimidine biosynthesis, tRNA maturation, inhibitor design, and structure/function relationships.
Microbial metabolism of energy-relevant and greenhouse gases (CO, CO2, methane) and xenobiotics (e.g., PCBs); regulation by and metabolism of CO in humans; and the roles of metal ions in biology, including the mechanisms of nickel, B12 , heme, and iron-sulfur enzymes. We use transient and steady-state kinetics, spectroscopy, and molecular biology to uncover mechanistic information.
The molecular mechanisms of how pathogenic bacteria produce and secrete a large capsule polysaccharide that enhances bacterial virulence. In particular, we focus on a regulatory tyrosine kinase and phosphatase in pathogenic E. coli. Techniques include enzyme kinetics and X-ray crystallography.
Structure-function studies of proteins using X-ray crystallography with an emphasis on complex enzymes and the replication proteins of flaviviruses and alphaviruses.
Chemical and structural biology of enzymes that covalently modify histones, transcription factors, and other nuclear proteins. Our current research focuses on elucidating the molecular mechanisms underlying the specificities of histone methyltransferases and demethylases and on developing new assays and reagents to characterize these enzymes.
Mechanistic structure-function relationships in ncRNAs using single molecule tools, for biomedical, bioanalytical and nanotechnological applications. The ncRNAs we study range from small RNA enzymes, such as the hammerhead, hairpin and hepatitis delta virus ribozymes with potential use in human gene therapy and relevance to human disease, to large RNA-protein complexes, such as RNA interference machinery involved in gene regulation and virus suppression.