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Scientific Report 2008


Biological Chemistry

P.G. Schultz, E. Brustad, P. Chen, C. Dambacher, D. Groff, J. Grünewald, J. Guo, B. Hutchins, S. Kazane, H. Lee, J.-S. Lee, C. Liu, C. Lyssiotis, C. Melancon, J. Mills, R. Perera, F. Peters, S. Schiller, M. Sever, L. Supekova, T. Young

Although chemists are remarkably adept at the synthesis of molecular structure, they are far less sophisticated in designing and synthesizing molecules with defined biological or chemical functions. Nature, on the other hand, has produced an array of molecules with remarkably complex functions, ranging from photosynthesis and signal transduction to molecular recognition and catalysis. Our aim is to combine the synthetic strategies and biological processes of Nature with the tools and principles of chemistry to create new molecules with novel chemical and biological functions. By studying the properties of the resulting molecules, we can gain new insights into the molecular mechanisms of complex biological and chemical systems.

For example, we have shown that the tremendous combinatorial diversity of the immune response can be chemically reprogrammed to generate selective enzymelike catalysts. We have developed antibodies that catalyze a wide array of chemical and biological reactions, from acyl transfer to redox reactions. Characterization of the structure and mechanisms of these catalytic antibodies has led to important new insights into the mechanisms of biological catalysis. In addition, the detailed characterization of the properties and structures of germ-line and affinity-matured antibodies has revealed fundamental new aspects of the evolution of binding and catalytic function, in particular, the role of structural plasticity in the immune response. Most recently, we have focused on in vitro evolution methods that involve the development of novel chemical screens and selections for identifying metalloantibodies with proteolytic activity.

In addition, we are extending this combinatorial approach to many other problems, including the generation of novel cellular reporters, the ab initio evolution of novel protein domains, and the synthesis of structure-based combinatorial libraries of small heterocycles. The libraries of small heterocycles are being used in conjunction with novel cellular and organismal screens to identify molecules that modulate the activity of important proteins involved in such cellular processes as differentiation, proliferation, and signaling. Indeed, we have identified molecules that control adult and embryonic stem cell differentiation and stem cell self-renewal and that reprogram lineage-committed cells to alternative cell fates. We are using x-ray crystallographic and biochemical studies, together with mRNA profiling technology and genetic complementation, to characterize the mode of action of these compounds and to study their effects on cellular processes and in animal models of regeneration. More recently, we extended such studies to a variety of genetic and neglected diseases (e.g., malaria, type 1 diabetes, spinal muscular atrophy, sickle cell anemia). We are also developing and applying modern genomics tools (e.g., cell-based phenotypic screens of arrayed genomic cDNA and short interfering RNA libraries) and proteomics tools (mass spectrometric phosphoprotein profiling) to a variety of significant biomedical problems in cancer biology, neurodegenerative disease, and virology. In addition, we are investigating the role and regulation of noncoding RNAs.

We have also developed a general biosynthetic method that makes it possible to site specifically incorporate unnatural amino acids into proteins in vitro and in vivo. Using this method, we effectively expanded the genetic code of living organisms by adding new components to the existing biosynthetic machinery. We have genetically encoded amino acids with novel spectroscopic and chemical properties (e.g., metal-binding, sulfated, fluorescent, photocross-linking, and photoisomerizable) in response to unique 3- and 4-base codons. These amino acids are being used to explore protein structure and function both in vitro and in vivo, create novel therapeutic agents and biomaterials, and evolve proteins with novel properties. This approach has been developed for Escherichia coli, yeast, and mammalian cells, and we are now extending it to multicellular organisms. Our results have removed a billion-year constraint imposed by the genetic code on the ability to chemically manipulate the structures of proteins during translation.


Galkin, A.V., Melnick, J.S., Kim, S., Hood, T.L., Li, N., Li, L., Xia, G., Steensma, R., Chopiuk, G., Jiang, J., Wan, Y., Ding, P., Liu, F., Sun, F., Schultz, P.G., Gray, N.S., Warmuth, M. Identification of NVP-TAE684: a potent, selective. and efficacious inhibitor of NPM-ALK [published correction appears in Proc. Natl. Acad. Sci. U. S. A. 104:2025, 2007]. Proc. Natl. Acad. Sci. U. S. A. 104:270, 2007.

Liu, Y., Kern, J.T., Walker, J. R. Johnson, J., Schultz, P.G., Luesch, H. A genomic screen for activators of the antioxidant response element. Proc. Natl. Acad. Sci. U. S. A. 104:5205, 2007.

Gumireddy, K., Sun, F., Klein-Szanto, A.,J., Gibbins, J.M., Saunders, A., Schultz, P.G., Huang, Q. In vivo selection for metastasis promoting genes in the mouse. Proc. Natl. Acad. Sci. U. S. A. 104:6696, 2007.

Liu, W., Alfonta, L., Mack, A.V., Schultz, P.G. Structural basis for the recognition of para-benzoyl-L-phenylalanine by evolved aminoacyl-tRNA synthetases. Angew. Chem. Int. Ed. 46:6073, 2007.

Xie, J., Supekova, L., Schultz, P.G. A genetically encoded metabolically stable analogue of phosphotyrosine in Escherichia coli. ACS Chem. Biol. 2:474, 2007.

Wang, J., Schiller, S., Schultz, P.G. A biosynthetic route to dehydroalanine-containing proteins. Angew. Chem. Int. Ed. 46:6849, 2007.

Xie, J., Liu, W., Schultz, P.G. A genetically encoded bidentate, metal-binding amino acid. Angew. Chem. Int. Ed. 46:9239, 2007.

Supekova, L., Supek, F., Lee, J., Chen, S., Gray, N., Pezacki, J., Schlapbach, A., Schultz, P.G. Identification of human kinases involved in hepatitis C virus replication by small interference RNA library screening. J. Biol. Chem. 283:29, 2008.

Lemke, E.A., Summerer, D., Geierstanger, B.H., Brittain, S.M., Schultz, P.G. Control of protein phosphorylation with a genetically encoded photocaged amino acid. Nat. Chem. Biol. 3:769, 2007.

Guo, J., Wang, J., Anderson, J.C., Schultz, P.G. Addition of an α-hydroxy acid to the genetic code of bacteria. Angew. Chem. Int. Ed. 47:722, 2008.


Peter G. Schultz, Ph.D.

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