Structure/function relationships of nucleic acids
RNA-targeted drug discovery
Novel RNA-based antimicrobial targets
Roles of modified nucleosides in tRNA
Nuclear magnetic resonance (NMR) of RNA
RNA-RNA and RNA-protein interactions
RNA, the macromolecule central to the control and expression of genes, is the new target of disease intervention, and a macromolecular tool relevant to all of biology. We are interested in the structure-function relationship of RNAs, including the design of new RNAs. Particularly, we investigate how the structure and chemistry of RNA allows it to function in protein synthesis and in control of gene expression in pathogenic bacteria. To do this we utilize nuclear magnetic resonance (NMR) and other biophysical methods, as well as biochemical, molecular, and chemical techniques.
Structure-function relationships of nucleic acids, such as that of tRNA in protein synthesis, are fundamental to all cell and molecular biology. In order to probe the structure-function relationships of RNAs as potential targets or tools, we have developed methods for the introduction of native, non-natural, and stable isotope labeled nucleosides. We have found that modified nucleosides in tRNA play an important structural and functional role both within the tRNA molecules and in tRNA anticodon recognition of select codons at the wobble position. Modified nucleosides alter codon "wobble," enhance ribosome binding, explain programmed translational frameshifting, are determinants for aminoacyl-tRNA synthetase recognition, and are involved in human immunodeficiency virus (HIV) selection of a specific human tRNA to prime reverse transcription.
RNA-targeted drug discovery and the characterization of novel RNA-based antimicrobial targets has become a predominant focus of the lab. With antibiotic resistance on the rise, there is a demand for the characterization of new “druggable” targets for small molecule intervention. With our expertise in both structural and biophysical characterization of RNA, as well as cell biology and microbiology, we are able to design novel inhibitors and test them in vivo, and for toxicity in mammalian cell culture.