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Dr. William F. DeGrado - George W. Raiziss Professor of Biochemistry and Biophysics |
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Research Summary
Dr. DeGrado's research focuses on molecular design as an approach to understanding macromolecule structure and function. Dr. DeGrado's primary research interest is in the de novo design of proteins, in which one attempts to design proteins from first principals. This approach critically tests his understanding of protein folding and function, while also laying the groundwork for the design of proteins with properties not precedented in nature. The de novo design of proteins has proven to be a useful approach for understanding the features in a protein sequence that cause them to fold into their unique three-dimensional structures. In addition, the DeGrado lab has recently been able to prepare a variety of functionally interesting proteins that bind redox-active cofactors, DNA, and transition metals. A second area of interest is the design of small molecules that inhibit the interaction of cells with the extracellular matrix by binding to a class of membrane proteins known as integrins. Such compounds have potential as antithrombotic and anti-inflammatory drugs, depending on the integrin that is targeted. A third area of interest is in the structure and function of membrane-active peptides. This laboratory has prepared peptides that act as ion channels, antibiotics and fusogenic agents. Tools used by the group in these projects include computer-aided molecular design, organic synthesis, peptide synthesis, protein expression, phage peptide libraries, NMR, and various forms of optical spectroscopy. Selected Publications Choma, C., H. Gratkowski, J.D. Lear and W.F. DeGrado (2000) Asparagine-mediated self-association of a model transmembrane helix. Nature, Structural Biology, 7:161-166. Lombardi, A., C.M. Summa, S. Geremia, L. Randaccio, V. Pavone and W.F. DeGrado (2000) Retrostrutural analysis of metalloproteins: application to the design of a minimal model for diiron proteins. Proc. Natl. Acad. Sci. 97: 6298-6305. Talaga, D. S., W.L. Lau, H. Roder, J. Tang, Y. Jia, W.F. DeGrado and R.M. Hochstrasser (2000) Dynamics and folding of single two-stranded coiled-coil peptides studied by fluorescent energy transfer confocal microscopy. Proc. Natl. Acad. Sci .97: 13021-13026 Kochendoerfer G.D., D. Salom, J.D. Lear, R. Wilk-Orescan, S.B.H. Kent and W.F. DeGrado (1999) Total chemical synthesis of the integral membrane protein Influenza A virus M2: role of its C-terminal domain in tetramer assembly. Biochemistry 38: 11905-11913. Lu, H. S. M., M. Volk, Y. Kholodenko, E. Gooding, R.M. Hochstrasser and W.F. DeGrado (1997) Aminothio-tyrosine disulfide, an optical trigger for initiation of protein folding. J. Am. Chem. Soc. 119: 7173-7180. Pinto, L. H., G.R. Dieckmann, C.S. Gandhi, C.G. Papworth, J. Braman, M.A. Shaughnessy, J.D. Lear, R.A. Lamb and W.F. DeGrado (1997) A functionally defined model for the M2 proton channel of influenza: a virus suggests a mechanism for its selectivity. Proc. Natl. Acad. Sci. USA 94: 11301-11306. Ogihara, N. L., M.S. Weiss, W.F. DeGrado and D. Eisenberg (1997) The structure of the designed trimeric coiled coil coil-Va-Ld: implications for engineering crystals and supramolecular assemblies. Protein Science 6:78-86 Bennett, J. S., C. Chan, G. Vilaire, S.A. Mousa and W.F. DeGrado (1997) Agonist-activated avb3 on platelets and lymphocytes binds to the matrix protein osteopontin. J. Biol. Chem. 272: 8137-8140. Bryson, J. W., S.F. Betz, H.S. Lu, D.J. Suich, H.X. Zhou, K.T. O'Neil and W.F. DeGrado (1996) Protein design, a hierarchic approach. Science 270: 935-941. |