Biological Chemistry and Molecular Pharmacology
Our research is concerned with structures of proteins and protein complexes and their functional roles. We use NMR spectroscopy, other biophysical techniques, computational tools and small molecule inhibitors to reveal mechanisms and cellular significance of protein interactions.
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, eIF5, eiF4H, eIF4A, and small-molecule inhibitors.
We also seek to understand mechanisms of T-cell function from structural studies. This includes the abTCR and the associated CD3 complexes. In addition, we try to understand mechanisms of downstream signaling at the level of nuclear translocation of nuclear factor of activated T cells (NFAT) through de-phosphorylation by calcineurin.
How transcriptional activators interact with co-activators from the Mediator family is another theme pursued in collaboration with the group of Anders Näär (MGH). We are determining structures of complexes, search for inhibitors of such interactions and validate the compounds as anti-cancer or anti-fungal agents.
We are interested in protein-protein interactions in apoptosis. These include molecules from the Bcl-2 family and the mitochondrial membrane protein VDAC. Recently we have developed procedures for incorporating membrane proteins in covalently circularized phospholipid nanodiscs creating stable membrane protein preparations usable for numerous membrane protein studies.
Furthermore, we work on non-ribosomal peptide synthetases and try to understand mechanisms by which building blocks of natural products are selected, processed and cyclized.
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).
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).
D. P. Frueh, H. Arthanari, A. Koglin, D. Vosburg, A. E. Bennett, C. T. Walsh, and G. Wagner, Dynamic thiolation-thioesterase structure of a non-ribosomal peptide synthetase. Nature, 454, 903-906 (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).
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).
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),