Brian F. P. Edwards, Ph.D.
ProfessorArea of interest: Structural biology Ph.D. Harvard University, Cambridge, MA, 1975 http://www.med.wayne.edu/biochem/~xray/ e-mail: bedwards@med.wayne.edu Tel: 313-577-1506 |
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ProfessorArea of interest: Structural biology Ph.D. Harvard University, Cambridge, MA, 1975 http://www.med.wayne.edu/biochem/~xray/ e-mail: bedwards@med.wayne.edu Tel: 313-577-1506 |
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My laboratory uses X-ray crystallography to elucidate the structure-function relationships of proteins. Presently, our projects cluster into three areas:
Blood clotting. Thrombin is the central protein in hemostasis defined as the containment of circulating blood. Unregulated activity brings death by heart attack or stroke. A major goal of my laboratory is to understand how the successive conversion of prothrombin to meizothrombin to thrombin is regulated by physiological effectors. During clotting, activated platelets release PF4, a chemokine and clotting regulator. In some patients, stable PF4:heparin complexes induce an immune reaction that destroys the patient’s platelets. Other members of the chemokine family of homologous proteins function in inflammation, wound healing, and HIV infection. We are elucidating the functional determinants of chemokine interaction through structural analysis of native proteins, selected mutants, and relevant complexes.
Arsenate reduction. The R773 plasmid of Escherichia coli encodes a system for the active extrusion of toxic arsenic from cells as arsenite. Arsenate reductase converts arsenate (AsV) to arsenite (As III
), thus extending bacterial resistance to the pentavalent state of arsenic. We are using the crystal structure of the reductase to identify the binding sites for substrates and products and to delineate the mechanism.Pyrimidine biosynthesis. The synthesis of pyrimidine nucleic acids is essential for cell division. Consequently, the enzymes in this pathway are potential targets for anticancer drugs. We have crystallized several of these enzymes from a thermophilic bacterium and are now working to determine their structure-function relationships.
Selected publications:
Purcarea, C., Martin, P., Vickrey, J., Guy, H. I., Edwards, B. F. P., Evans, D. R. Cloning, expression, purification, crystallization and preliminary X-ray analysis of the Dihydroorotase from the thermophilic bacteria Aquifex Aeolicus. Acta Crystallogr. D Biol. Crystallogr. 58:154-156, 2002.
Martin, P., DeMel, S., Shi, J., Gladysheva, T., Gatti, D., Rosen, B. R., Edwards, B. F. P. Insights into the Structure, Solvation, and Mechanism of ArsC Arsenate Reductase, a Novel Arsenic Detoxification Enzyme. Structure, 9:1071-1081, 2001.
Henschen, A., Theodor, I., Edwards, B. F. P., Pirkle, H. Crotalase, a fibrinogen-clotting venom enzyme: primary structure and evidence for a fibrinogen recognition exosite different from thrombin. Thrombosis and Haemostasis. 81:81-86, 1999.
Massova, I., Martin, P. D., Bulychev, A., Kocz, R., Doyle, M., Edwards, B. F. P. Mobashery, S. Templates for design of inhibitors for serine proteases: application of the program DOCK to the discovery of novel inhibitors for thrombin. Bioorganic and Medicinal Chem. Lett. 8;2463-2466, 1998.
Massova, I., Pirkle, H., Edwards, B. F. P., Mobashery, S. Insights into the three-dimensional structure of crotalase: implications for biological activity and substrate specificity. Bioorganic and Medicinal Chem. Lett. 7:3139-3144, 1997.
Martin, P., Malkowski, M. G., Box, J., Esmon, C. T., Edwards, B. F. P. New insights into the regulation of the blood clotting cascade derived from the X-ray crystal structure of bovine meizothrombin desF1 in complex with PPACK. Structure. 5:1681-1693, 1997
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