We use X-ray crystallography to study the three-dimensional structures of proteins. The structural information is used for drug design, protein engineering, to understand catalytic mechanisms, and to explore protein evolution. Our group is also involved in the development of tools and techniques associated with synchrotron radiation, especially multiple wavelength anomalous diffraction (MAD) and single wavelength anomalous diffraction (SAD). Our main projects include studies of enzymes involved in purine nucleotide metabolism and pyrimidine nucleotide metabolism, studies of enzymes involved in co-factor biosynthesis, especially thiamin biosynthesis, and enzymes involved in polyamine and purine biosynthesis.
Because of the role of purine and pyrimidine nucleotide metabolism in diseases such as cancer and viral infection, many of the enzymes involved are targets for drug design. We have focused considerable effort on nucleoside phosphorylases, which are found in both purine and pyrimidine pathways. Purine nucleoside phosphorylase is required for T-cell development while thymidine phosphorylase has been associated with angiogenesis. In collaboration with Professor Eric Sorscher, University of Alabama Medical School and Dr. William Parker, Southern Research Institute, we also study bacterial purine nucleoside phosphorylase because of its application in prodrug activation via gene therapy. Together with our collaborator, Professor JoAnne Stubbe at MIT, we are investigating enzymes involved in purine biosynthesis. Systematic investigation of an entire biochemical pathway provides important clues about protein evolution.
We are also interested in co-factor biosynthesis. We are currently focusing our efforts in this area on thiamin biosynthesis. Many of the reactions catalyzed by these enzymes involve unprecedented chemistry and elucidation of catalytic mechanism is a major goal. By studying these enzymes, we have also discovered interesting evolutionary links to other pathways. Our main collaborator for these studies is Professor Tadhg Begley of Cornell.
Polyamines have been implicated in many biological processes. Because of their alternating positive and hydrophobic regions, polyamines are able to bind to protein and nucleic acids in unique ways. Production of polyamines is highly regulated and is correlated with the cell cycle. We study enzymes of polyamine biosynthesis in collaboration with Professor Anthony Pegg of the Pennsylvania State University College of Medicine, Dr. Wayne Guida of the University of South Florida, and Drs. John Secrist and William Waud of the Southern Research Institute. We hope to use the structures of these enzymes to design novel anticancer and antiparasitic drugs.
Finally, we are interested in synchrotron radiation and its application in macromolecular crystallography. The Northeastern Collaborative Access Team (NE-CAT), with Professor Ealick as director, is operating two undulator beamlines, one of which is already capable of microdiffraction experiments, at Sector 24 of the Advanced Photon Source (APS) at Argonne National Laboratory in Argonne, Illinois, and is in the process of building an additional bending magnet experimental stations. Please see our website http://necat.chem.cornell.edu for more information about this project.
Please see our group webpage http://arginine.chem.cornell.edu for additional information about our personnel, publications, and structures.
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Jurgenson CT, Burns KE, Begley TP, and Ealick SE. Crystal Structure of a Sulfur Carrier Protein Complex Found in the Cysteine Biosynthetic Pathway of Mycobacterium tuberculosis. Biochemistry 47: 10354-10364 (2008).
Morar M, Hoskins AA, Stubbe J, and Ealick SE. Formylglycinamide Ribonucleotide Amidotransferase from Thermotoga maritima: Structural Insights into Complex Formation. Biochemistry 47:7816-7830 (2008).
McCulloch KM, Kinsland C, Begley TP, and Ealick SE. Structural Studies of Thiamin Monophosphate Kinase in Complex with Substrates and Products. Biochemistry 47: 3810-3821 (2008).
Soriano EV, Rajashankar KR, Hanes JW, Bale S, Begley TP and Ealick SE. Structural Similarities between Thiamin-Binding Protein and Thiaminase-I Suggest a Common Ancestor. Biochemistry 47:1346-1357 (2008).
Zhang Y, White RH and Ealick SE. Crystal Structure and Function of 5-Formaminoimidazole-4-carboxamide-1-β-D-ribofuranosyl 5-Monophosphate Synthetase from Methanocaldococcus jannaschii. Biochemistry 47:205-217 (2008).
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