We study the molecular basis of cell regulatory processes by using the tools of structural biology and biochemistry to examine proteins and protein complexes associated with these processes. X-ray crystallography enables us to obtain the three-dimensional structures of individual proteins and their interactions with other molecules. Biochemistry and molecular biology allow us to study properties that can be correlated to protein structure and function. Our efforts largely center on protein complexes involved in nucleic acid regulatory processes.

The introduction of exogenous double-stranded RNA (dsRNA) into a cell can trigger the gene silencing process called RNA interference or RNAi. Although there has been remarkable progress in unraveling the components of the RNAi machinery, we are just beginning to understand how they work at the molecular level. Therefore, we embarked on structural and biochemical studies of these proteins. For example, by solving the structure of a full-length Argonaute protein, a key component in the RNAi machinery, we recently identified Argonaute as “Slicer”, the enzyme that cleaves the mRNA as directed by the siRNA. These studies enhance not only our understanding of this important pathway, but should also improve the practical use of the RNAi technology as an experimental tool for gene knockdown technology.

Another system is DNA replication initiation in papillomaviruses. Papillomaviruses are small DNA tumor viruses that cause benign and malignant lesions in humans. In order to gain insight into the mechanism of viral replication initiation, we are studying the two viral proteins that are required for viral replication, the initiator protein E1 and the transcription factor E2, and their complexes. Proteins involved in viral replication are particularly attractive drug targets, and having their detailed three-dimensional structure would greatly facilitate efficient design of antiviral drugs.