Bushweller, John H.

John Bushweller

John H. Bushweller

Primary Appointment

Professor, Molecular Physiology and Biological Physics


  • BA, Chemistry, Dartmouth College
  • PhD, Chemistry, University of California, Berkeley, CA
  • Postdoc, Eidgenössische Technische Hochschule, Zürich, Switzerland

Contact Information

PO Box 800736
Telephone: 434-243-6409
Email: jhb4v@virginia.edu
Website: http://www.people.virginia.edu/%7Ejhb4v/

Research Interests

Structural and Functional Basis for Oncogenesis; Targeted Drug Development; Structural Studies of Membrane Proteins

Research Description

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 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 carrying out structural and functional studies of the oncoprotein forms of the two subunits of CBF that are associated with leukemia. We have now extended these studies to the MLL protein, a key epigenetic regulator that is the target of chromosomal translocations in leukemia which are particularly poor prognosis. Structure-Based Drug Discovery. We are using structure-based drug design to develop small molecule inhibitors of the oncoprotein forms of core binding factor as well as of MLL fusion proteins. Our focus is on the development of highly targeted molecules which inactivate the oncoprotein form and have minimal side-effects. Such agents have significant potential for the treatment of the associated leukemias. Structural Studies of Membrane Proteins. A third 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 determined the structure of the 4 TM enzyme DsbB by solution NMR which established a paradigm for tackling this class of proteins by NMR. We are currently examining additional technical improvements in this area as well as targeting several new systems for structure determination. Please see our group website for additional information: http://www.people.virginia.edu/~jhb4v/

Selected Publications