John H. Bushweller
Professor
B.A. Dartmouth College 1984;
Ph.D. University of California, Berkeley 1989;
NIH Postdoctoral Fellow, ETH-Zurich, Switzerland
Structural and Functional Basis for Oncogenesis
Our lab is fundamentally interested in understanding, from a structural and
biophysical perspective, the functioning of proteins involved in regulating
transcription, particularly those involved in the dysregulation associated
with the development of cancer. Structural and functional characterization
of the native forms of these proteins and their relevant complexes via NMR
spectroscopy, X-ray crystallography, and a variety of other techniques provides
a baseline of understanding. Subsequent characterization of the oncoprotein forms then
forms then provides a detailed understanding of the molecular mechanism of oncogenesis
associated with altered forms of these proteins. Such knowledge leads to novel
avenues for the design of therapeutic agents to treat the cancers associated
with these particular oncoproteins.
Our current focus is structural studies of a novel transcriptional enhancer
referred to as the core-binding factor (CBF). This heterodimeric protein is
essential for hematopoietic development. Gene translocations associated with
the genes coding for the two subunits of CBF produce novel fusion proteins
which have been implicated as playing a role in more than 30% of acute
leukemias. We are pursuing structural studies of the oncoprotein forms of the
two subunits of CBF that are associated with leukemia as well as functional
studies to elucidate the role of specific interactions in leukemogenesis.
This represents an overall effort to provide a structural basis for the properties
of these proteins and their altered forms that can be translated into novel
strategies for therapeutic development.
Chemical Biology Targeting Leukemia
A second area of focus for the lab is the development of novel small molecule
inhibitors of these leukemia translocation proteins. To this end, we are using
structure-aided drug design tools to identify initial lead compounds to inhibit
well-validated protein-protein interactions involving these proteins. These
are optimized using medicinal chemistry approaches and subsequently tested
both in leukemia cell lines and in appropriate mouse models of the associated
diseases.
Structural Studies of Membrane Proteins
An additional area of focus for the lab is the application of solution NMR
methods to the structure determination of membrane proteins. The vast majority of
drug targets are membrane-embedded proteins. This class of proteins has presented
significant challenges for structure determination by any method. We recently
completed the structure determination of the largest membrane protein to be solved
by NMR spectroscopy to date. This structure established a paradigm for tackling
this class of proteins by solution NMR. We are currently examining additional
technical improvements in this area as well as targeting several new systems for
structure determination.
Recent Publications
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