My laboratory has two major research focuses. The first is to understand the pre-mRNA splicing machinery on a molecular level, using X-ray crystallography in combination with molecular biological, biochemical, and biophysical approaches. Splicing of pre-mRNA is essential for gene expression in all eukaryotes. In higher eukaryotes such as mammals, an average of 95% of the nucleotides in the primary transcript (pre-mRNA) of a protein-encoding gene are introns. These introns need to be precisely removed by splicing before the mRNA can be transported out of the nucleus and translated. Even a single nucleotide error causes catastrophic consequences. Aberrant splicing contributes to at least 15% of human genetic disorders and causes many other diseases such as cancer. A thorough understanding of the pre-mRNA splicing pathway may provide useful approaches for human disease therapy. The splicing of pre-mRNA is carried out through two transesterification reactions catalyzed by spliceosome, a huge macromolecular complex (approximately 4.8 MDa) that contains five RNAs and numerous (over 145 in human) protein splicing factors. Among the large amount of protein factors, protein/protein, and protein/RNA complexes in the spliceosome, many of them await detailed structural analyses. Crystallographic analyses (in combination with molecular biology, biochemical, and biophysical approaches) of these individual proteins and complexes in the spliceosome will provide valuable insight into intron recognition, spliceosome formation, and catalytic mechanism.

Our second research area focuses on structure-based drug design targeting bacterial signal transduction systems and transcriptional complexes critical in breast tumorigenesis. Structure-based drug design is a valuable tool in modern drug discovery which can save years of time and millions of dollars compared to traditional trial-and-error drug development processes. Similar approaches have successfully generated drugs that battle various human diseases such as HIV. We hope our structure-based drug design efforts contribute to the development of new antibiotics and anti-cancer drugs.