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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