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.
Geldenhuys WJ, Leeper TC, Carroll RT. “mitoNEET as a novel drug target for mitochondrial dysfunction.” Drug Discov Today. pii: S1359-6446 (2014)
Bilinovich SM, Davis, CM, Morris DL, Ray LA, Prokop JW, Buchan GJ, Leeper TC. “The C-terminal domain of SRA1p has a fold more similar to PRP18 than to an RRM and does not directly bind to the SRA1 RNA STR7 region.” Journal of Molecular Biology 426:1753-1765. (2014).
Herrick RS, Ziegler CJ, Leeper TC. “Structure and function in organometallic•protein complexes.” Journal of Organometallic Chemistry, 751, 90-110 (2014).
Marhabaie M, Leeper TC, Blackledge TA. “Protein Composition Correlates with the Mechanical Properties of Spider ( Argiope trifasciata ) Dragline Silk.” Biomacromolecules. 15, 20-29 (2014).
Wu J, Zhao C, Hu R, Lin W, Wang Q, Zhao J, Bilinovich SM, Leeper TC, Li L, Cheung HM, Chen S, Zheng J. “Probing the weak interaction of proteins with neutral and zwitterionic antifouling polymers.” Acta Biomaterialia 10, 751-760 (2014).
Panzner MJ, Bilinovich SM, Parker JA, Bladholm EL, Ziegler CJ, Berry SM, Leeper TC. “Isomorphic deactivation of a Pseudomonas aeruginosa oxidoreductase: The crystal structure of Ag(I) metallated azurin at 1.7 Å.” Journal of Inorganic Biochemistry. 128, 11-16 (2013)