• B.S. (1992) Texas A&M University at Galveston
• Ph.D. (1998) Biochemistry and Cell Biology, Rice University
• Postdoctoral Fellow (1998-1999), Biochemistry and Cell Biology, Rice University
• Postdoctoral Fellow (1999-2004), Pharmacology and Toxicology, University of Texas Medical Branch
Research Interests
Drug design and metabolism; structure/function of cytochromes P450; inhibition
While most enzymes are specific for a single substrate, a few are much more versatile. The main interest of the laboratory involves the ability of cytochromes P450 to both bind and metabolize a number of chemicals that are very different in size, shape, and stereochemistry. Within an organism, the presence of a number of these versatile enzymes is largely responsible for the body's ability to eliminate foreign chemicals including drugs, environmental substances, and carcinogens. Introduction to Cytochromes P450
Major questions include:
• How does the three-dimensional structure of a P450 recognize, bind, and metabolize multiple chemically diverse substrates?
• By what mechanism can two different P450s act on a common substrate but differentiate between other chemicals that only one of them can metabolize?
• How do selective inhibitors interact with protein structure in these versatile enzymes?
To investigate these and related questions, the laboratory uses methods in molecular biology (site-directed mutagenesis, recombinant protein expression and purification), biochemistry (assays of protein function, various spectroscopic methods), and x-ray crystallography. Projects in the lab involve the human P450s 2A13 and 2E1, which constitute a model system for examining two enzymes with both overlapping and distinct substrates. The general hypothesis is that comparison of molecular structure and biochemistry across different P450s will assist in the identification of protein physical and chemical features responsible for differences in substrate metabolism. These characteristics can then be used to understand and predict substrate specificity and to design selective inhibitors for clinical use.
Previous work by Dr. Scott involved solving several structures of the rat liver cytochrome P450 2B4. This movie shows an interpolation between the atomic positions of a crystal structure of cytochrome P450 2B4 in an "open" confirmation (PDB: 1PO5) and a crystal structure of 2B4 in a "closed" conformation with the inhibitor 4-(4-chlorophenyl)imidazole (cyan) bound to the heme (red). Residues highlighted in purple (helices F', G', and G) and those highlighted in orange (helices B' through C) are substantially relocated to open and close a cleft from the protein surface to the buried active site, while the remainder of the protein is relatively static. Animation generated using the Yale Morph Server (Krebs and Gerstein. 2000. Nucleic Acids Res 28: 1665-75.)
For More Information, Please Contact:
Emily E. Scott, Ph.D.
Department of Medicinal Chemistry
4067 Malott Hall
Tel: 785-864-5559
FAX: 785-864-5326
Email: eescott@ku.edu
