Bushweller, John H.

John H. Bushweller

John H. Bushweller

Primary Appointment

Professor, Molecular Physiology and Biological Physics

Education

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

Contact Information


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.

Structure-Based Drug Discovery. We are using structure-based drug design

to develop small molecule inhibitors of the oncoprotein forms of core binding

factor. 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 OmpA by solution NMR which 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.

Please see our group website for additional information: http://www.people.virginia.edu/~jhb4v/

Selected Publications