BBS Faculty Member - Gerhard Wagner

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
Lab Members: 20 postdoctoral fellows, 2 graduate students, 1 technician, 1 faculty assistant



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, and small-molecule inhibitors.

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

We are interested in protein-protein interactions in apoptosis and their action and interactions in the mitochondrial membrane. This includes studies of the human Voltage-Dependant Anion Channel (VDAC) and its interactions with Bcl-xL, Bak or other factors of the outer mitochondrial membrane. We also have a general interest in structures of integral membrane proteins.

In a collaboration with Chris Walsh we study structures of non-ribosomal peptide synthetases and want to understand their mechanisms of action and selectivity.

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.



Last Update: 8/22/2013



Publications

J. K. Thakur, H. Arthanari, F. Yang, S.-J. Pan, X. Fan, J. Breger, D. P. Frueh, K. Gulshan, D. Li, E. Mylonakis, K. Struhl, W. S. Moye-Rowley, B. P. Cormack, G. Wagner, A. M. Näär: A Nuclear Receptor-Like Pathway Regulating Multidrug Resistance in Fungi. Nature, 452, 604-609 (2008).

S. Hiller, R. G. Garces, T. J. Malia, V. Y. Orekhov, M. Colombini, G. Wagner: Solution structure of the integral human membrane protein VDAC-1 in detergent micelles, Science 321, 1206- 1210 (2008).

D. P. Frueh, H. Arthanari, A. Koglin, D. Vosburg, A. E. Bennett, C. T. Walsh, and G. Wagner, “Dynamic T-TE domain communication in the enterobactin non-ribosomal peptide synthetase, Nature, 454, 903-906 (2008).

A. Marintchev, K. A. Edmonds, B. Marintcheva, E. Hendrickson, M. Oberer, C. Suzuki, B. Herdy, N. Sonenberg, G. Wagner: The topology of the human eIF4A/4G/4H complex and the regulation of helicase activity, Cell, 136, 447-460. (2009).



© 2013 by the President and Fellows of Harvard College