|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.