Irene Weber, Professor, Structural Biology, Georgia State University Chemistry

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Irene Weber
Professor, Structural Biology
D.Phil., Oxford University, UK (1978)

Dr. Irene Weber
Department of Chemistry
Georgia State University
P.O. Box 4098
Atlanta, Georgia 30302-4098


Phone:	404-413-5563
Fax:	404-413-5505
Office:	503 Science Annex
Email:	iweber@gsu.edu

Research Projects

The major research theme of my laboratory is to understand the mode of action of key regulatory proteins at the molecular level by applying the techniques of bioinformatics, biochemistry and crystallography to study the structure and function of protein-ligand complexes. Current research projects include:

Studies of drug resistance in HIV and comparative studies of other retroviruses. HIV and other retroviruses cause AIDS and cancer in humans and other animals. We are studying the crystal structures and enzymatic activities of drug resistant mutants of HIV proteases in order to understand the molecular basis for drug resistance. Comparative studies on structure and substrate specificity are being performed on related proteases from Rous sarcoma virus and HTLV.

The Tcl1 family of proteins involved in chronic lymphocytic leukemias. We have determined the crystal structure of human Mtcp1, one of the Tcl1 family of oncoproteins. These proteins fold into an eight-stranded beta barrel of unique topology. However, their role in lymphoid cell biology is not clear. Therefore, we are investigating the structure and potential ligands of Tcl1, Mtcp1 and other family members.

Cyclic nucleotide gated channels. Previously, we had built a molecular model of the cGMP-binding domain of the cGMP-gated retina channel. Currently, we are investigating the crystal structure and ligand binding properties of these channel domains in the form of soluble chimeras.

Bioinformatics and Structural genomics. We are members of the South Eastern Collaboratory for Structural Genomics. This is a pilot study to develop high throughput methods for determining the atomic structures of all proteins expressed in a genome. We have been improving methods for representation and analysis of protein-ligand complexes for many years.

Human glucokinase and mutations involved in type II diabetes. We have built models to understand how glucokinase binds to its two substrates, glucose and ATP. These glucokinase models have proved invaluable for understand the effects of glucokinase mutations involved in development of Mature Onset Diabetes of the Young.

Representative Publications

Fu, Z.-Q., Du Bois, G.C., Song, S.P., Kulikovskaya, I., Virgilio, L., Rothstein, J.L., Croce, C.M., Weber, I.T. and Harrison, R.W. "Crystal Structure of MTCP-1: Implications for Role of TCL-1 and MTCP-1 in T Cell Malignancies." (1998) Proc. Natl. Acad. Sci. USA 95, 3413-3418.
Weber, I.T. and Harrison, R.W. "Molecular Mechanics Analysis of Drug Resistant Mutants of HIV Protease" (1999) Protein Eng. 12, 469-474.
Mahalingam, B., Cuesta-Munoz, A., Davis, E.A., Matschinsky, F.M., Harrison, R.W. and Weber, I.T. "Structural Model of Human Glucokinase in Complex with Glucose and ATP: Implications for the Mutants that Cause Hypo- and Hyperglycemia" (1999) Diabetes 48, 1698-1705.
Tozser, J., Zahuczky, G., Bagossi, P., Louis, J.M., Copeland, T.D., Oroszlan, S., Harrison, R.W. and Weber, I.T. "Comparison of the substrate specificity of the human T- cell leukemia virus and human immunodeficiency virus proteinases." (2000) Eur. J. Biochem. 267, 6287-6295.
Mahalingam, B., Louis, J.M., Hung, J., Harrison, R.W. and Weber, I.T. "Structural implications of drug resistant mutants of HIV-1 protease: High resolution crystal structures of the mutant protease/substrate analog complexes." (2001) Proteins, 43, 455- 464.
Petock, J.M., Wang, Y.-F., DuBois, G.C., Harrison, R.W. and Weber, I.T. "Effects of Different Post-crystallization Soaking Conditions on the Diffraction of Mtcp1 Crystals." (2001) Acta Crystallog. D57, 763-765.
Scott, S.-P., Weber, I.T., Harrison, R.W., Carey, J. and Tanaka, J.C. "A Functioning Chimera of the Cyclic Nucleotide-Binding Domain from the Bovine Retinal Rod Ion Channel and the DNA-Binding Domain from Catabolite Gene-Activating Protein." (2001) Biochem. 40, 7464-7473.
Petock, J.M., Torshin, I.Y., Wang, Y.-F., DuBois, G.C., Croce, C.M., Harrison, R.W. and Weber, I.T. "Crystal Structure of Murine Tcl1 at 2.5�Resolution and Structural Comparison of Tcl1 Family of Novel Oncoproteins." (2001) Acta Crystallog. D57, 1545-1551.
Mahalingam, B., Boross, P., Wang, Y.-F., Louis, J.M., Fischer, C., Tozser, J., Harrison, R.W. and Weber, I.T. "Combining Mutations in HIV-1 Protease to Understand Mechanisms of Resistance." (2002) Proteins 48, 107-116.
Torshin, I.Y., Weber, I.T., Harrison, R.W. "Geometric criteria of hydrogen bonds in proteins and identification of "bifurcated" hydrogen bonds." (2002) Protein Eng., 15, 359-363.
Petock, J.M., Torshin, I.Y., Wang, Y.-F., DuBois, G.C., Croce, C.M., Harrison, R.W. and Weber, I.T. "Crystal Structures Of Tcl1 Family Oncoproteins And Their Conserved Surface Features." (2002) TheScientificWorld Journal, 2, 1876-1884.
Feher, A., Weber, I.T., Bagossi, P., Boross, P., Mahalingam, B., Louis, J.M., Torshin, I.Y., Harrison, R.W. and Tozser, J. Effect of sequence polymorphism and drug resistance on two HIV-1 Gag processing sites. (2002) Eur. J. Biochem., 269, 4114-4129.
Torshin, I.Y., Harrison, R.W., Weber, I.T. "Close pairs of carboyxlates: a possibility of multicenter hydrogen bonds in proteins. (2003) Protein Eng., 16, 201-207.
Torshin I., Weber I.T., Harrison R.W. Net charge center as the simplest model of a protein identifies up to 100% of active/binding site residues. (2003) Med. Sci. Monit. 9, BR289-301.
Liu, P., Wang, Y.-F., Ewis, H., Abdelal, A., Lu, C.D., Weber, I.T. "Crystallization and preliminary X-ray diffraction data for the carboxylesterase Est30 from Bacillus stearothermophilus." (2003) Acta Crystallog. D, 59, 1472-1473.
Koh, Y., Nakata, H., Maeda, K., Ogata, H., Bilcer, G., Devasamundam, T., Kincaid, J.F., Boross, P., Wang, Y.-F., Tie, Y., Volarath, P., Gaddis, L., Harrison, R.W., Weber, I.T., Ghosh, A.K., Mitsuya, H. A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI) UIC-94017 (TMC114) potent against multi-PI- resistant HIV in vitro. (2003) Antimicrob. Agent Chemother. 47, 3123-3129.
Petock, J.M., Torshin, I.Y., Weber, I.T., Harrison, R.W. Analysis of protein structures reveals regions of rare backbone conformation at functional sites. (2003) Proteins 53, 872-879.
Daniel, R., Myers, CB., Kulkosky, J., Taganov, K., Greger, JG., Merkel, G., Weber, IT., Harrison, RW., Skalka, AM. Characterization of a naphthalene derivative inhibitor of retroviral integrases. AIDS Res. Hum. Retroviruses. (2004) 20, 135-144.
Tie, Y., Boross, P.I., Wang, Y.-F., Gaddis, L., Hussain, A.K., Leshchenko, S., Ghosh, A.K., Louis, J.M., Harrison, R.W., Weber, I.T. High Resolution Crystal Structures of HIV-1 Protease with a Potent Non-peptide Inhibitor (UIC-94017) Active against Multi-Drug Resistant Clinical Strains. (2004) J. Mol. Biol. 338, 341-352.
Mahalingam, B., Wang, Y.-F., Boross, P.I., Tozser, J., Louis, J.M., Harrison, R.W., Weber, I.T. Crystal structures of HIV protease V82A and L90M mutants reveal changes in indinavir binding site. (2004) Eur. J. Biochem. 271, 1516-1524.
Harrison, R.W., and Weber, I.T. Molecular Models of Human Glucokinase and the Implications for Glycemic Diseases. (2004) Frontiers in Diabetes, Vol. 16: Glucokinase and Glycemic Disease, From Basics to Novel Therapeutics. Eds. Matschinsky, F.M. and Magnuson, M.A., Basel, Karger, pp 135-144.
Bagossi, P., Kadas, J., Miklossy, G., Boross, P., Weber, I.T., Tozser, J. Development of a microtiter plate fluorescent assay for inhibition studies on the HTLV-1 and HIV-1 proteinases. (2004) J. Virol. Methods 119, 87-93.
Liu, P., Wang, Y.-F., Ewis, H., Abdelal, A., Lu, C.D., Harrison, R.W., Weber, I.T. Covalent Reaction Intermediate revealed in Crystal Structure of the Geobacillus stearothermophilus Carboyxlesterase Est30. (2004) J. Mol. Biol. 342, 551-556.