My group is interested in the atomic structures (interatomic distances, bond angles, and topology) of biomolecules associated with chromatin and chromatin modifying factors. Some of these factors generate heritable epigenetic effects that are important to biological processes such as cellular development, tumorigenesis, and aging.
Recently, a number of non-coding ribonucleic acid molecules (RNAs) have been implicated in chromatin modification. We are particularly keen to study the modes of RNA recognition in these ribonucleoprotein (RNP) complexes. These RNPs are particularly exciting for the simple fact that RNA's role in epigenetic programming is still somewhat poorly understood.
As a general technique, nuclear magnetic resonance spectroscopy (NMR) is appealing because it permits structure determination under physiologically relevant solution conditions, and also because it is a powerful tool for probing biophysical phenomena at the atomic level. Small molecule drug-like fragment screens and second site equilibrium binding events can be easily observed via NMR and thus nicely complement the obvious structural biology applications.
Using both NMR and molecular genetics, we are investigating a number of specific factors: yeast and human telomerase RNA-protein interactions, centromeric histone variants, and RNA-polycomb protein complexes. We believe that a complete understanding of the biochemistry of RNA-protein interactions at atomic detail will be vital to understanding the biology of epigenetic change.
MJ Panzner, SM Bilinovich, JA Parker, EL Bladholm, CJ Ziegler, SM Berry, TC Leeper. “Isomorphic Deactivation of a Pseudomonas aeruginosa Oxidoreductase: The Crystal Structure of Ag(I) Metallated Azurin at 1.7 Å” Journal of Inorganic Biochemistry, DOI:10.1016/j.jinorgbio.2013.07.011, (2013)
RS Herrick, CJ Ziegler, TC Leeper. “Structure and function in organometallic•protein complexes.” Journal of Organometallic Chemistry. DOI:10.1016/j.jorganchem.2013.07.004 [Special 50th Anniversary Issue], (2013).
TA Blackledge, M Kuntner, M Marhabaie, TC Leeper, I Agnarsson, “Biomaterial evolution parallels behavioral innovation in the origin of orb-like spider webs.” Scientific Reports 2:833 (2012).
MJ Morris, KL Wingate, J Silwal, TC Leeper, S Basu. “The porphyrin TmPyP4 unfolds the extremely stable G-quadruplex in MT3-MMP mRNA and alleviates its repressive effect to enhance translation in eukaryotic cells.” Nucleic Acids Res. 40, 4137–4145 (2012)
JW Prokop, TC Leeper, ZH Duan, A Milsted. "Amino acid function and docking site prediction through combining disease variants, structure alignments, sequence alignments, and molecular dynamics: A study of the HMG domain." BMC Bioinformatics. 13 (Suppl 2):S354 (2012).
MJ Panzner, SM Bilinovich, WJ Youngs, TC Leeper, "Silver Metallation of Hen Egg White Lysozyme: X-ray Crystal Structure and NMR Studies," Chem. Commun., 47 (46) 12479-12481 (2011).
TC Leeper, S. Zhang, W. C. Van Voorhis, P. J. Myler and G. Varani, “Comparative analysis of glutaredoxin domains from bacterial opportunistic pathogens.” Acta Cryst. F67, 1141-1147 (2011).
SL Binkley, TC Leeper, RS Rowlett, RS Herrick, CJ Ziegler, "Re(CO)(3)(H(2)O)(3)(+) binding to lysozyme: structure and reactivity." Metallomics, 3, 909-916 (2011).
Lunde BM, Reichow SL, Kim M, Suh H, TC Leeper, Yang F, Mutschler H, Buratowski S, Meinhart A, Varani G. “Cooperative interaction of transcription termination factors with the RNA polymerase II C-terminal domain.” Nature Structural and Molecular Biology (2010).
TC Leeper, Qu X, Lu C, Moore C, Varani G. “Novel protein-protein contacts facilitate mRNA 3'-processing signal recognition by Rna15 and Hrp1.” Journal of Molecular Biology 401, 334-49 (2010).
Office: KNCL 206