Professor of Medicinal Chemistry
Post.Doc., University of Texas Medical Branch
Ph.D., Rice University
B.S., Texas A&M University
Research Focus: Structure/function of human cytochrome P450 enzymes
The Scott lab focuses on human cytochrome P450 (P450) enzymes with key roles in human health. Many are critical in the clearance of drugs, carcinogens, and toxins. In this area, our goals are to understand small molecule activation and deactivation in the body to increase safety and efficacy. Other human P450 enzymes control the levels of important endogenous molecules. The Scott lab exploits these enzymes as targets for drug design in specific diseases like prostate and breast cancer.
An overarching theme in our studies is to determine how the three-dimensional structure of an individual cytochrome P450 binds and interacts with chemically diverse substrates and inhibitors. To find answers to this question we employ ever-expanding methods in molecular biology, recombinant protein expression and purification, spectroscopy, enzymology, analytical mass spectroscopy, synthetic chemistry, X-ray crystallography and protein NMR.
Determining structural features responsible for drug metabolism by different P450 enzymes
Our research is probably best known for generating the first X-ray structures of many different human membrane P450 enzymes. Most are the result of a dedicated artisan process dealing with special considerations of the stability, solubility, and flexibility of these enzymes during expression, purification, and crystallization. The results are used to define structural features responsible for the overlapping, yet distinct substrate selectivities of different P450 enzymes. This information is then used to understand the metabolism of new drugs without explicitly determining structures of each complex.
Drug development: Cytochrome P450 enzymes in human steroidogenesis
Cytochrome P450 enzymes dominate human steroidogenesis. Inhibition of CYP17A1, a key enzyme in the production of sex steroids, is a relatively new target for the treatment of prostate cancer and breast cancer. Our contributions to the field have been to determine the first structure of CYP17A1, investigate enzyme mechanism, show that inhibitors then in human prostate cancer clinical trials bind very differently than proposed, and explore new routes for drug improvement.
P450 interactions with catalytic partner proteins
All P450 catalysis requires P450 interaction with NADPH-cytochrome P450 reductase, with catalysis further modulated by binding of cytochrome b5. Complex interactions among the three proteins control human physiology, but essentially no high-resolution structural information is available. Understanding and modulating such interactions is an orthogonal approach to modulating human metabolism of drugs and endogenous biomolecules.
Research in the Scott lab ranges from the basic science and structural biology aspects of ligand binding, protein/protein interactions, and catalysis to real-world applications in drug metabolism and drug design.
Scott Research Group
||MERIT Award, NIH/NIGMS
||North American New Investigator Award in honor of James R. Gillette, The International Society for the Study of Xenobiotics|
||Early Career Achievement Award, Drug Metabolism Division, American Society for Pharmacology and Experimental Therapeutics
Yadav, R., Petrunak, E.M., Estrada, D.F., and Scott, E.E. (2016) Structural insights into the function of steroidogenic cytochrome P450 17A1. Mol. Cell. Endocrinol. (in press)
Estrada, D.F., Laurence, J.S., and Scott, E.E. (2015) Cytochrome P450 17A1 interactions with the FMN domain of its reductase as characterized by NMR. J. Biol. Chem. 291:3390-4003.
Petrunak, E.M., DeVore, N.M., Porubsky, P.R., and Scott, E.E. (2014) Structures of human steroidogenic cytochrome P450 17A1 with substrates. J. Biol. Chem. 289: 32952-32964.
Estrada, D.F., Skinner, A.L., Laurence, J.S., and Scott, E.E. (2014) Human cytochrome P450 17A1 conformational selection: Modulation by ligand and cytochrome b5. J. Biol. Chem. 289:14310-14320.
Blake, L.C., Roy, A., Neul, D., Schoenen, F.J., Aubé, J. and Scott, E. E. (2013) Benzylmorpholine analogs as selective inhibitors of lung cytochrome P450 2A13 for the chemoprevention of lung cancer in tobacco users. Pharm. Res. 30: 2290-2302.
Walsh, A.A., Szklarz, G.D. and Scott, E. E.(2013) Human cytochrome P450 1A1 structure and utility in understanding drug and xenobiotic metabolism. J. Biol. Chem. 288:12932-12943.
Stephens, E.S., Walsh, A.A., and Scott, E. E. (2012) Evaluation of inhibition selectivity for human cytochrome P450 2A enzymes. Drug Metab. Dispos. 40:1797-1802.
DeVore, N.M. and Scott, E. E. (2012) Cytochrome P450 17A1 structures with prostate cancer drugs abiraterone and TOK-001. Nature 482:116-119.