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.

The primary structural focus is on how eukaryotic translation initiation regulates the fate of cells. In particular, we study 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 have anti-tumor activity. We are also working on other factors involved in eukaryotic translation initiation, such as eIF2, eIF4H, eIF5B, eIF5 and eIF4A, and small-molecule inhibitors.

In a collaboration with Anders Näär we study interactions between transcriptional activators and co-activators. This includes the interaction of the SREBP transcriptional activator with Med15 component of the human Mediator, and the transactivation domain of fungal Pdr1p interacting with the Gal11 KIX domain. Inhibitors of these interactions we discovered with high-throughput screening are being improved and tested for their potential as anti-cancer drugs and agents against pathogenic yeast.

We also seek to understand mechanisms of T-cell function from structural studies. This includes the
abTCR and the associated CD3 proteins, and the downstream signaling proteins calcineurin and NFAT.

We are interested in protein-protein interactions in apoptosis and their action 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.

We study structures of non-ribosomal peptide synthetases to understand their mechanisms of action and selectivity.

A major effort in the laboratory is on optimizing NMR technologies. This includes developing optimized pulse sequences, methods for non-uniform sampling and suitable processing software. We also maintain a facility for NMR-based screening of fragment libraries to identify ligands of macromolecules that could be linked for obtaining tighter binders.



Last Update: 6/3/2014



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).



© 2014 by the President and Fellows of Harvard College