University of South Florida

Cancer Biology Ph.D. Program at the

Training

M.S. University of Bochum (Germany) 1988
Ph.D. Max-Planck Research Unit for Structural Molecular Biology, Hamburg, Germany, 1991
Postdoctoral Training - Max-Planck Research Unit, 1991-1996

Research Interests
Research from the Schönbrunn laboratory focuses on the elucidation of the structure-activity relationship of medicinally important proteins. We use protein crystallography combined with methods in biochemistry, molecular biology and medicinal chemistry to explore proteins at the atomic level. Our aim is to identify "weak sites" in those proteins that can be targeted by new inhibitors with potential as future drugs. The spectrum of prospective drug targets under investigation in our laboratory is diverse and growing continuously:

• Antibiotic targets such as MurA and EPSP synthase.

• Anti-cancer targets such as CDK2/cyclin A and glucometabolic enzymes.

• Neurodegenerative disease targets such as calpain.

• Male-contraceptive targets such as soluble adenylate cyclase.

We generally follow two routes towards the discovery of novel inhibitors; both these approaches become interconnected if the target protein can be crystallized. The empirical approach involves the development of an assay suitable for high-throughput screening (HTS) of hundreds of thousands of small organic compounds for inhibitory activity. Thus discovered inhibitors (hits) will be scrutinized by structure-activity relationship (SAR) and kinetic studies until the most potent inhibitors with drug-like properties (leads) have been identified. The second route is the rational design of inhibitors based on the 3D atomic structure of the target protein. First, crystallization conditions suitable for reproducible growth of X-ray quality crystals need to be established. Then, the atomic structure of the target protein will be solved by crystallographic methods, bound with ligands such as substrates, known inhibitors or newly discovered HTS hits and leads. With this information in hand, we perform several computational studies (in silico design), such as molecular docking, to identify chemical scaffolds that satisfy the criteria for high inhibitory potential. During the entire inhibitor discovery process we closely collaborate with researchers of various disciplines, from synthetic organic chemistry to cell biology, to devise strategies for the optimization of the best inhibitors with respect to drug-like properties. Our expertise enables us to not only thoroughly characterize the molecular mode of action of inhibitors on proteins; we also perform mechanistic studies, for example to trap reaction intermediate states of enzyme-catalyzed reactions. Furthermore, we investigate the resistance of target proteins to known inhibitors. These studies complement the rational design approach, at the same time providing valuable information about the relationship of the protein’s structure and function.

Search for publications by:
This search will be conducted at the US National Library of Medicine (NLM) and PubMed.

Selected Publications:

Funke, T., Healy-Fried, M.L., Han, H., Alberg, D.G., Bartlett, P.A. and Schönbrunn, E. (2007). Differential Inhibition of Class I and Class II EPSP Synthases by Tetrahedral Reaction Intermediate Analogs. Biochemistry 46:13344-13351

Healy-Fried, M.L., Funke, T., Han, H., Priestman, M. and Schönbrunn, E (2007). Molecular Basis for the Glyphosate-Tolerance of EPSP synthase from E. coli, Induced by Mutations of Proline101. J. Biol. Chem. 282: 32949-32955

Wang, A., Zeng, Y., Han, H., Weeratunga, S., Morgan,B.N., Moënne-Loccoz, P., Schönbrunn, E. and Rivera, M. (2007). Biochemical and Structural Characterization of Pseudomonas aeruginosa Bfd and FPR: Ferredoxin NADP Reductase and not Ferredoxin is the Redox Partner of Heme Oxygenase under Iron-Starvation. Biochemistry 46:12198-12211

Funke, T., Han, H., Healy-Fried, M.L., Fischer, M., and Schönbrunn, E. (2006). Molecular Basis for the Herbicide Resistance of Roundup Ready Crops. Proc. Natl. Acad. Sci. USA 103: 13010-13015

Li, Q. Hanzlik, R.P., Weaver, R.F. and Schönbrunn, E. (2006). The Molecular Mode of Action of a Covalently Inhibiting Peptidomimetic on the Human Calpain Protease Core. Biochemistry, 45:701-708

Priestman, M.A., Funke, T., Singh, I.M., Crupper, S.S. and Schönbrunn, E. (2005). 5-Enolpyruvylshikimate-3-phosphate synthase (EPSPS) from Staphylococcus aureus is Insensitive to Glyphosate. FEBS Lett. 579: 728-732

Eschenburg, S., Priestman, M.A., Abdul-Latif, F.A., Delachaume, C., Fassy, F., and Schönbrunn, E. (2005). A Novel Inhibitor That Suspends the Induced-Fit Mechanism of UDP-N-acetylglucosamine Enolpyruvyl Transferase (MurA). J. Biol. Chem. 280: 14070-14075

Priestman, M.A., Healy, M.L., Becker, A., Alberg, D.G., Bartlett, P.A., Lushington, G.H., and Schönbrunn, E. (2005). The Interaction of Phosphonate Analogs of the Tetrahedral Reaction Intermediate with 5-Enolpyruvylshikimate-3-phosphate synthase (EPSPS) in Atomic Detail. Biochemistry 44: 3241-3248

Priestman, M.A., Healy, M.L., Funke, T., Becker, A. and Schönbrunn, E. (2005). Molecular Basis for the Glyphosate-Insensitivity of the Reaction of 5-Enolpyruvylshikimate 3-Phosphate Synthase with Shikimate.” FEBS Lett. 579: 5773-5580

Eschenburg, S., Priestman, M.A. and Schönbrunn, E. (2005). Evidence That the Fosfomycin Target Cys115 in UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA) is Essential for Product Release. J. Biol. Chem. 280: 3757-3763

Eschenburg, S., Kabsch, W., Healy, M.L., and Schönbrunn, E. (2003). A New View of the Mechanisms of UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA) and 5-Enolpyruvylshikimate-3-phosphate Synthase (AroA) Derived from X-ray Structures of Their Tetrahedral Reaction Intermediate States. J. Biol. Chem. 278: 49215–49222

Schönbrunn, E., Eschenburg, S., Schloss, J.V., Shuttleworth, W.A, Amrhein, N., Evans J.N.S., and Kabsch, W. (2001). Interaction of the Herbicide Glyphosate with its Target Enzyme EPSP Synthase in Atomic Detail. Proc. Natl. Acad. Sci. USA 98: 1376-1380

Schönbrunn, E., Eschenburg S., Luger K., Kabsch W., and Amrhein N. (2000). Structural Basis for the Interaction of the Fluorescence Probe 8-Anilino-1-Naphthalene Sulfonate (ANS) with the Antibiotic Target MurA. Proc. Natl. Acad. Sci. USA, 97: 6345-6349

Schönbrunn, E., Eschenburg S., Krekel F., Luger K., and Amrhein, N. (2000). Role of the Loop Containing Residue 115 in the Induced-Fit Mechanism of the Bacterial Cell Wall Biosynthetic Enzyme MurA. Biochemistry 39: 2164-2173

Eschenburg S. and Schönbrunn, E. (2000) “Comparative X-ray Analysis of the Unliganded Fosfomycin Target MurA. PROTEINS: Structure, Function, and Genetics 40: 290-298