Bushweller

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 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. 

One current focus is structural studies of a novel transcription factor 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 have carried out structural (NMR spectroscopy and X-ray crystallography) and functional studies of the oncoprotein forms of the two subunits of CBF that are associated with leukemia to gain an understanding of their roles in the development of leukemia. Another focus area is on fusion proteins involving the transcription factor MLL, which are implicated in a high percentage of pediatric leukemias. We also have an effort focused on the transcription factor ERG which has a critical role in leukemia as well as prostate cancer.

Our chemical biology efforts focus on the development of highly targeted small molecule inhibitors of the oncoprotein forms of CBF and MLL. Using structural information on the proteins, various screening approaches, NMR and fluorescence-based assays, and medicinal chemistry, we have developed the first small molecule inhibitors of these proteins. This is a collaborative effort with outside investigators at the University of Pennsylvania, University of Massachusetts, Cornell, and Loyola University. As these are transcription factor targets which have been viewed as “undruggable," our successful development of inhibitors targeting them is opening up new avenues for drug development.

A third focus for the lab has been 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 completed the structure determination of the largest helical membrane protein to be solved by NMR spectroscopy at the time. This structure established a paradigm for determining structures of this class of proteins by solution NMR. We are currently examining additional technical improvements in this area as well as targeting new systems for structure determination.

 

Recent Publications

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First Name: 
John H.
Image: 
UVA Chemistry People John Bushweller
People Type: 
Computing ID: 
jhb4
Phone: 
434-243-6409
Office Address: 
Room 4233, Pinn Hall
Education: 

B.A. Dartmouth College, 1984

Ph.D. University of California, Berkeley, 1989

NIH Postdoctoral Fellow, ETH-Zurich, Switzerland,1990-1992

Research Interests: 
Protein structure and dynamics, NMR spectroscopy, structure-based drug design