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James D. Baleja, Ph.D. Associate Professor, Tufts Department of Biochemistry B.Sc. Biochemistry, University of Manitoba Ph.D. Biochemistry, University of Alberta |
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Links:ResearchLab MembersRecent Publications |
Research Summary:My laboratory uses nuclear magnetic
resonance (NMR) spectroscopy and other
spectroscopic methods to gain an understanding of protein-protein interactions.
We are also interested in structure-based approaches to develop inhibitors
of protein-protein interactions. Although most drugs target proteins
with enzymatic activity a few target protein-protein interactions.
A classic example is Colchicine.
Study of the structure and function
of medically important proteins provides the wherewithal to design molecular
agents to combat or inhibit the mechanisms that allow devastating diseases
or disorders to occur and proliferate. The laboratory also contributes
methodological advances to NMR spectroscopy. The laboratory provides
for an environment to learn NMR through a problem-based learning approach
in a weekly NMR discussion group. We also characterize proteins by circular
dichroism on a JASCO J-810 spectrophotometer and by fluoresence spectroscopy
on a Jobin-Yvon Fluorolog-3 fluorimeter. We can also quantify molecular
interactions directly by using isothermal titration calorimetry on a
Microcal VP-ITC calorimeter and through sedimentation equilibrium measurements
on a Beckman XL-I
ultracentrifuge.
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Design of Papillomavirus Inhibitors
The papillomavirus causes several diseases, ranging
from the common wart to a more virulent strain that produces cervical cancer,
a costly and devastating disease that is the second leading cause of death in
women worldwide. The laboratory is using NMR to analyze the three-dimensional
structures of two viral proteins. The E2 protein takes over the host cell and controls the
growth of the virus by binding to DNA. The E6 protein degrades the p53 tumor
suppressor and has an effect on cell cycle proteins. We have determined the
structures for several cellular proteins that bind E6. Through computer
analysis and modeling, we aim to design drugs that disable the triggering mechanism
of the virus. Some of this work is in collaboration with Elagen, Inc., a biotechnology
company.
Role of the EH domain in Endocytosis and Cellular Proliferation
We are also studying proteins involved in endocytosis
and signal transduction, with a particular emphasis on the role of calcium
and dimerization on their activity. The growth and development of cells relies
on signals that are carried from the surface of a cell to the nucleus. These
signals are based on interactions between specialized protein molecules that
occur in a specific order or pathway. One signal
pathway starts with a peptide hormone called EGF that starts a cascade
of interactions between proteins that ultimately result in cellular proliferation.
This is important because in normal cells, the activities of the proteins
are in balance, whereas in cancerous cells they are out of control. For example,
in nearly half the patients with colon cancer, there is too much active Ras,
and in some breast cancer patients, there is too much EGF receptor. The Reps
protein links the EGF receptor and Ras to changes that accompany the conversion
of cells from normal to cancerous. By examining the
shape of its EH domain we can clarify the rules that govern its control
and help to devise strategies to alter its activity. Equally important is
the dynamics of a protein, in which we understand the range
of motions present in a protein.
The Role of Self-selection in B-cell Development
For more details, please see the publications below.
