Gerhard Wagner

Department of Biological Chemistry and Molecular Pharmacology
Harvard Medical School
Building C1, Room 112
240 Longwood Avenue
Boston, MA 02115
Tel: (617) 432-3213
Fax: (617) 432-4383
Email: wagner@hms.harvard.edu
12 postdoctoral fellows, 4 graduate students, 2 technical staff, 1 administrator

Our research is concerned with structures of proteins and protein complexes. We use NMR spectroscopy, computational tools and small molecule inhibitors to study function and cellular significance of protein interactions. We are also interested in biomarker identification and measuring metabolite levels for characterizing and monitoring human disease.

The primary structural focus is on how eukaryotic translation initiation regulates the fate of cells. In particular, we are interested in the interaction of the cap-binding proteins eIF4E with the mRNA cap, the scaffold protein eIF4G, and the regulatory 4E-BPs, and how these interactions are related to cell transformation and apoptosis. To address this, we have identified small-molecule inhibitors of the eIF4E/eIF4G interaction and found that these may have anti-tumor activity. We are also working on other factors involved in eukaryotic translation initiation, such as eIF2, eIF2B, eIF5B, eIF5 and eIF4A.

We also seek to understand mechanisms of T-cell function from structural studies. This includes the human T-cell adhesion glycoprotein CD2, the αßTCR and proteins that are associated with these complexes or are involved in T-cell signaling. These include CD3, CD2-BPs, proteins that bind cytoplasmic tails of T-cell receptor proteins, calcineurin and NFAT.

We are interested in protein-protein interactions in apoptosis. These include caspase-recruitment domains and DNA-fragmentation factors, Bcl-xL, Bcl-2, Bid, and the mitochondrial protein VDAC. We are also interested in identifying small-molecule inhibitors of anti-apoptotic proteins. We want to characterize their interaction using experimental and computational tools and investigate their effect on cellular function.

Recently, we became engaged in efforts to characterize the metabolite levels in human body fluids using NMR and mass spectroscopy. Currently, we are focused on chronic myologeneous leukemia (CML) as a model disease. We find that certain metabolic pathways are upregulated due to the presence of the Philadelphia chromosome, and could show the effect of drug treatment on metabolite levels.

References:

• J.D. Gross, N.J. Moerke, T. Von der Haar, A. A. Lugovskoy, A.B. Sachs, J. McCarthy, and G. Wagner: Structure and Assembly of the eIF4GI-eIF4E-cap complex. Cell, 115, 739-750 (2003).
• F. Yang, B. W. Vought, J. S. Satterlee, Z.-Y. J. Sun, J. L. Watts, A. K. Walker, R. DeBeaumont, R. M. Saito, S. G. Hyberts, S. Yang, C. Macol, L. Iyer, R. Tjian, S. van den Heuvel, A. C. Hart, G. Wagner, A. M. Näär: An ARC/Mediator subunit required for SREBP gene activation and regulation of cholesterol and fatty acid homeostasis, Nature, 442, 700-704 (2006).
• T. Malia, G. Wagner: NMR Structural Investigation of the Mitochondrial Outer Membrane Protein VDAC and its Interaction with Anti-apoptotic Bcl-xL, Biochemistry, 46, 514-525 (2007).
• N. J. Moerke, H. Aktas, H. Chen, S. Cantel, Mikhail Y. Reibarkh, A. Fahmy, J. D. Gross, A. Degterev, J. Yuan, M. Chorev, J. A. Halperin, G. Wagner: Small Molecule Inhibition of the Interaction Between the Translation Initiation Factors eIF4E and eIF4G. Cell, 128, 257-267 (2007).