Professor
Graduate Admissions Chairman

Department of Biochemistry and Molecular Biology
Indiana University School of Medicine
John D. Van Nuys Medical Science Building
635 Barnhill Drive, Room 4032D
Indianapolis, Indiana 46202-5126

Phone: (317) 278-8486
Facsimile: (317) 274-4686
E-mail: mgeorgia@iupui.edu
Chemistry Web Site

B.S. in Biochemistry with honors, 1984, Indiana University, Bloomington, IN
Ph.D. in Biochemistry, 1990, University of California, Los Angeles, CA

Area of Study

X-ray crystallographic, biochemical, and thermodynamic studies of protein-nucleic acid interactions involved in replication, nuclear export, and temporal gene expression.   More details...

Selected Recent Publications

Das, D. and Georgiadis, M. M. (2004) The crystal structure of the monomeric reverse transcriptase from Moloney murine leukemia virus, Structure 12, 819-829.

Crowther, R. L., Remeta, D. P., Minetti, C., Das, D., Montano, S. P., and Georgiadis, M. M. (2004) Structural and energetic characterization of nucleic acid binding to the fingers domain of Moloney murine leukemia virus reverse transcriptase. Proteins 57, 15-26.

Fingerman, I., Sutphen, K., Montano, S. P., Georgiadis, M. M., and Vershon, A. K. (2004) Characterization of critical interactions between Ndt80 and MSE-DNA defining a novel family of Ig-fold transcription factors. Nucl. Acids Res. 25, 2947-2956.

Crowther, R. L. and Georgiadis, M. M. (2005) The crystal structure of 5-keto-4-deoxyuronate isomerase from Eschericia coli. Proteins 61, 680-684.

Goodwin, K. D., Long, E. C., and Georgiadis, M. M. (2005) A host-guest approach for determining DNA-drug interactions: An example using netropsin. Nucl. Acids Res. 33, 4106-4116.

Goodwin, K. D., Lewis, M. A., Tanious, F. A., Tidwell, R. R., Wilson, W. D., Georgiadis, M. M., and Long, E. C. (2006) A high-throughput, high-resolution strategy for the study of site selective DNA binding agents: Analysis of a "highly-twisted" benzamidazole diamidine. JACS 128, 7846-7854.

Montano, S. P., Cote, M. L., Roth, M. J., and Georgiadis, M. M. (2006) Crystal structures of oligonucleotides including the integrase processing site of the Moloney murine leukemia virus. Nucleic Acids Res. 34,
5353-60.

Haag Breese, E., Uversky, V. N., Georgiadis, M. M., Harrington, M. A. (2006) The disordered amino-terminus of SIMPL interacts with members of the 70-kDa heat-shock protein family. DNA Cell Biol. 25, 704-14.

Tanious, F., Laine, W., Peixoto, P., Bailly, C., Goodwin, K. D., Lewis, M.; Long, E. C., Georgiadis, M. M., Tidwell, R., Wilson, D. W. (2007) Unusually strong binding to the DNA minor groove by a highly twisted benzimidazole-diphenylether: Induced fit and bound water. Biochemistry 46, 6944-6956.

Roman, Y., Oshige, M., Lee, Y.J., Goodwin, K., Georgiadis, M.M., Hromas, R.A. and Lee, S.H. (2007) Biochemical Characterization of a SET and Transposase Fusion Protein, Metnase: Its DNA Binding and DNA Cleavage Activity Biochemistry, 46, 11369-11376.

Goodwin, K. D, Lewis, M. A., Long, E. C., and Georgiadis, M. M. (2008) The crystal structure of DNA-bound Co(III)•bleomycin B₂: Insights on intercalation and minor groove binding, Proc. Natl. Acad. Sci. U.S.A, 105, 5052-5056.

Georgiadis, M. M., Luo, M., Gaur, R.K., Delaplane, S., Li, X., and Kelley, M. R. (2008) Evolution of the redox function in mammalian apurinic/apyrimidinic endonuclease. Mutat Res 643, 54-63.

Luo M, Delaplane S, Jiang A, Reed A, He Y, Fishel M, Nyland RL 2^nd, Borch RF, Qiao X, Georgiadis MM, Kelley MR (2008) Role of the multifunctional DNA repair and redox signaling protein Ape1/Ref-1 in cancer and endothelial cells: small-molecule inhibition of the redox function of Ape1, Antioxid Redox Signal, in press.

Glass, L.S., Nguyen, B., Goodwin, K.D., Dardonville, C., Wilson, W.D., Long, E.C. and Georgiadis, M.M. (2009) Crystal Structure of a Trypanocidal 4,4'-Bis(imidazolinylamino)diphenylamine Bound to DNA. Biochemistry 48, 5943-5952.

Long, E.C.#, Georgiadis, M.M., Goodwin, K.D., and Lewis, M.A. (2009) "New Approaches to analyzing the site selectivities and crysatl structure of DNA targeted metal complexes" in ACS Symposium Series 1012, Bioorganic Chemistry Cellular Systems and Synthetic Models, eds. Long, E.C. and Baldwin, M.J. pp. 63-80. (# corresponding author).

Glass, L., Bapat, A., Kelley, M.R., Georgiadis, M.M.#, and Long, E.C.# (2010) Semi-automated high-throughput fluorescent intercalator displacement-based discovery of cytotoxic DNA binding agents from a large compound library. Bioorg Med Chem Let 20, 1685-8. (#co-corresponding authors).

Luo, M., He, H., Kelley, M. R., and Georgiadis, M. M. (2010) Redox Regulation of DNA Repair: Implications for Human Health and Cancer Therapeutic Development. Antioxid Redox Signal 12, 1247-1269.

Bapat, A., Glass, L. S., Luo, M., Fishel, M. L., Long, E. C., Georgiadis, M. M., and Kelley, M. R. (2010) Novel small molecule inhibitor of Ape1 endonuclease blocks proliferation and reduces viability of glioblastoma cells. JPET 334, 988-998.

Goodwin, K. D., He, H., Imasaki, T., Lee, S. H., and Georgiadis, M. M. (2010) Crystal structure of the human Hsmar1-derived transposase in the DNA repair enzyme Metnase. Biochemistry 49, 5705-5713.

Mark R. Kelley*, Meihua Luo, April Reed, Dian Su, Sarah Delaplane, Richard F. Borch, Rodney L. Nyland II, Michael L. Gross, and Millie M. Georgiadis (2010) Functional analysis of new and novel analogs of E3330 that block the redox signaling activity of the multifunctional AP endonuclease/redox signaling enzyme APE1/Ref-1. Antioxid Redox Signal. Sep 27. [Epub ahead of print]

Victor J. Anciano Granadillo, Jennifer N. Earley, Sarah C. Shuck, Millie M. Georgiadis, Richard Fitch and John J. Turchi (2010) Small molecule inhibitors of Replication Protein A: Targeting OB-folds. J. Nucl Acids 2010, 304035.

Dian Su, Sarah Delaplane, Meihua Luo, Mark R. Kelley, Michael L. Gross, and Millie M. Georgiadis (2011) Interactions of APE1 with a redox inhibitor: Evidence for an alternate conformation of the enzyme. Biochemistry 50, 82-92. 

David O. Onyango, Arunasalam Naguleswaran, Sarah Delaplane, April Reed, Mark, R. Kelley, Millie M. Georgiadis, and William J. Sullivan Jr. (2011) Base excision repair apurinic/apyrimidinic endonucleases in apicomplexan parasite Toxoplasma gondii. DNA Repair, Feb. 23, Epub ahead of print.

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Research Interests

Research in my laboratory is directed toward understanding the role of protein-nucleic acid interactions in such fundamental biological processes as replication, nuclear export, and regulation of gene expression. Our approach is to integrate X-ray crystallographic studies with complementary biochemical studies. Current research efforts are focused on understanding in atomic detail two critical steps in the retroviral life cycle: (1) replication of the retroviral genome by reverse transcriptase and (2) nuclear export of unspliced retroviral transcripts including the constitutive transport element (CTE). These studies are related more generally to (1) the understanding of nucleic acid interactions that are important during replication through comparative analysis with related polymerases and (2) nuclear export of mRNA, which is mediated by the same host factor, Tap.

Reverse transcriptase (RT) is a relatively simple replicative polymerase by comparison with its mammalian counterparts and is therefore an ideal enzyme for studying the complicated process of polymerization. The epidemic outbreak of AIDS caused by human immunodeficiency virus (HIV) has focused a great deal of research efforts on HIV-1 RT. Drugs that are presently being used to treat AIDS patients include several inhibitors of HIV-1 RT, which continues to be a target for development of new inhibitors. We have focused our efforts on the Moloney murine leukemia virus (MMLV) RT, a related retroviral RT, with the goal of understanding the mechanism of the processive DNA synthesis and interactions with nucleic acid. Basic and detailed knowledge of catalysis and substrate interactions in RT will further efforts in the development of effective inhibitors.

We have determined X-ray crystallographic structures of several novel DNA complexes with the N-terminal fragment of MMLV RT. Our structural analysis and subsequent biochemical and retroviral work has led to the discovery of a novel binding site for nucleic acid and proposed mechanism for processive DNA synthesis. In addition, we have determined the crystal structure of the RNA-binding domain of human protein, Tap, which mediates nuclear export of mRNA. Through structure-based mutational analysis of this domain of Tap, we have proposed a novel RNA-interacting surface. Future structural work will focus on biologically relevant nucleic acid complexes of the full-length MMLV RT and human Tap protein.

A second area of interest is in understanding the role of nucleic acid interactions that regulate temporal gene expression during meiosis in yeast. This system serves as a model system for understanding mechanisms that control development in higher eukaryotes. We have recently determined the crystal structure of a novel DNA-binding domain from Ndt80, a transcriptional activator required for meiosis in yeast. Our structural studies revealed that Ndt80 has a novel structure as well as a novel DNA-binding motif and is the founding member of a new family of transcription factors including a human protein that has been reported to be highly expressed in invasive tumor cells. Future work on this project includes structural studies of relevant nucleic acid complexes with Ndt80 and other factors involved in the regulation of meiosis. We are also interested in characterizing additional members of this new family of transcription factors.