10591-Georgiadis, Millie
Faculty

Millie M. Georgiadis, PhD

Professor of Biochemistry & Molecular Biology

Address
635 Barnhill Drive
Medical Science, Room MS4032D

Indianapolis, IN 46202

Bio

Dr. Millie M. Georgiadis received her Ph.D. in 1990 in Biochemistry from the University of California, Los Angeles, working with Dr. Douglas Rees, now at the California Institute of Technology. Her graduate work focused on structure-function studies of the nitrogen fixing enzyme complex nitrogenase and culminated in the determination of the novel crystal structure of the nitrogenase iron protein.  Dr. Georgiadis pursued postdoctoral studies at Columbia University under the direction of Dr. Wayne Hendrickson, where she focused on the application of multiple wavelength anomalous dispersion (MAD) methods for phasing crystal structures. She determined a high resolution crystal structure of the N-terminal fragment of Moloney murine leukemia virus reverse transcriptase (MMLV RT) using mercury MAD phasing methods. Her structural and functional studies led to a steric mechanism to explain how a DNA polymerase like MMLV RT distinguishes dNTP from NTP substrates. As an Assistant Professor at Rutgers University, Dr. Georgiadis continued working on the structural basis of protein-nucleic acid interactions. Her laboratory determined crystal structures of MMLV RT bound to DNA, Ndt80, and Tap (NFX1) and developed a host-guest system for the crystallization and analysis of novel DNA sequences of interest. Dr. Georgiadis moved to Indiana University School of Medicine (IUSM) as an Associate Professor with tenure in 2002 and has since advanced to Full Professor. Her laboratory has expanded its interest in protein-nucleic acid and DNA-ligand interactions and, in several collaborative projects with colleagues at IUSM and IUPUI, has determined novel crystal structures of bleomycin bound to DNA, the catalytic domain of SETMAR, a chimeric fusion protein present only in anthropoid primates, the DNA-binding domain of SETMAR bound to its cognate TIR DNA sequence, and the C-terminal regulatory domain of GCN2, the eIF2 kinase that senses amino acid deprivation. Current cancer-related projects include genomic and structural studies of SETMAR to determine its role in normal and cancer cells and identification of small molecule modulators of the DNA repair protein, apurinic/apyrimidinic endonuclease 1 (APE1), for the treatment of cancer and chemo-induced peripheral neuropathy in collaboration with IUSM researchers. In a new synthetic biology project, the Georgiadis laboratory is pursuing structural characterization of artificial DNA and its interactions with DNA polymerases in collaboration with investigators from the Foundation for Applied Molecular Evolution.

Titles & Appointments

  • Professor of Biochemistry & Molecular Biology
  • Professor of Chemistry, School of Science
  • Education
    1990 PhD University of California, Los Angeles
    1984 BS Indiana University
  • Research

    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.

Research Labs

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Faculty Labs