[return to list] 
John  H.  Bushweller
Degree(s): Ph.D.
Graduate School: University of Californina, Berkeley
Primary Appointment: Professor of Molecular Physiology and Biological Physics
Research Interests:
Structural and Functional Basis for Oncogenesis; Targeted Drug Development; Structural Studies of Membrane Proteins

Email Address: jhb4v@virginia.edu
Biomedical Sciences Graduate Program(s)
  • Structural, Computational Biology and Biophysics
  • Molecular Medicine
  • Biochemistry, Molecular Biology and Genetics
    • 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
  • Charged Gels as Orienting Media for Measurement of Residual Dipolar Couplings in Soluble and Integral Membrane Proteins. Tomasz Cierpicki and John H. Bushweller. (2004) J. Am. Chem. Soc., 126, 16259-66.
  • CBFBeta Allosterically Regulates the Runx1 Runt domain by Shifting a Dynamic Conformational Equilibrium in the Runt Domain and DNA. Jiangli Yan, Yizhou Liu, Stephen M. Lukasik, Nancy A. Speck, and John H. Bushweller. (2004) Nat. Struc. Mol. Biol., 11, 901-906.
  • Synthesis and Evaluation of Substituted 4-Aryloxy- and 4-Arylsulfanyl-phenyl-2-aminothiazoles as Inhibitors of Human Breast Cancer Cell Proliferation. Michael J. Gorczynski, Susan L. Mooberry, John H. Bushweller, and Milton L. Brown. (2004) Bio. Med. Chem. Lett., 12, 1029-1036.
  • Altered Affinity of CBFBeta­SMMHC, Product of the Inv(16), for Runx1 Explains its Dominant Negative Activity and Role in Leukemogenesis. Stephen M. Lukasik, Lina Zhang, Takeshi Corpora, Sarah Tomanicek, Yuanhong Li, Mondira Kundu, Kari Hartman, P. Paul Liu, Thomas M. Laue, Rodney L. Biltonen, Nancy A. Speck, and John H. Bushweller. (2002) Nature Structural Biology, 9, 674-679.
  • PubMed Listings for this Faculty Member
    • Intranet Profile
    [To add/update Intranet profile information, read these instructions.]
    Contact Information
      Office Address: PO Box 800736, 1300 Jefferson Park Ave., Jordan Hall, 423, 
      Office Phone: +1 434-243-6409, +1 434-243-6402
      Fax Phone: +1 434-982-1616
      Home Phone: +1 434-245-0198
      Mobile Phone: +1 434-882-5907
      Web Site: http://www.people.virginia.edu/~jhb4v/

    Other Websites for this mentor:
    http://www.people.virginia.edu/%7Ejhb4v/

    (Find Out How to Update Your Faculty Profile)