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Scientific Report 2004


Chemistry




Biological Chemistry


P.G. Schultz, E.D. Akten, L. Alfonta, J.C. Anderson, M. Bose, E. Brustad, S. Chen, C. Cho, A. Cropp, A. Deiters, S. Ding, J. Gildersleeve, A. Glownia, J. Graziano, J. Grbic, J. Hong, Q. Huang, J. Liao, Q. Lin, J. Liu, H. Luesch, F. Marr, J. Melnick, J. Mills, K.H. Min, M. Mrukherji, P. Saviranta, L. Supekova, F. Tian, J. Turner, A. Willingham, X. Wu, J. Xie, J. Yang, H. Zeng, J. Zhang, Q. Zhang, L. Zheng

Although chemists are remarkably adept at synthesizing 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 hope to gain new insights into the molecular mechanisms of complex biological and chemical systems.

We showed that the tremendous combinatorial diversity of the immune response can be chemically reprogrammed to generate selective enzymelike catalysts. We 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 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 revealed fundamental new aspects of the natural evolution of binding and catalytic function, in particular, the role of structural plasticity in the immune response. Most recently, we focused on in vitro evolution methods that involve the development of novel chemical screens and selections for identifying mutants with enhanced function.

Our work on catalytic antibodies redirects natural combinatorial diversity to produce new function. We are extending this combinatorial approach to many other problems, including the generation of sequence-specific recombinases, small-molecule regulators of DNA transcription, and the ab initio evolution of novel protein domains. We are also generating structure-based combinatorial libraries of small molecules, including purine, pyrimidine, and fatty acid derivatives. These libraries are being used in conjunction with novel cellular and organismal screens to identify important proteins involved in such cellular processes as differentiation, proliferation and signaling. Indeed, we have identified molecules that control the fate of stem cell differentiation and that dedifferentiate committed cells. We are using x-ray crystallographic and biochemical studies, together with genomics experiments with gene chip arrays and genetic complementation, to characterize the mode of action of these compounds and to study their effects on cellular processes. We are also developing modern genomics tools (genomic cDNA and small interfering RNA libraries) and proteomics tools (mass spectrometric phosphoprotein profiling) and are applying them to a variety of important biomedical problems in cancer biology, neurodegenerative disease, stem cell differentiation, and viral infectivity.

We also developed a general biosynthetic method that can be used to site specifically incorporate unnatural amino acids into proteins in vitro and in vivo. Using this method, we effectively expanded the genetic code of bacteria and yeast by adding new components to the biosynthetic machinery of living cells. We added more than 30 amino acids with novel spectroscopic and chemical properties (e.g., keto- and heavy atom–containing amino acids, photocross-linking and photoisomerizable amino acids) to the genetic codes of Escherichia coli, yeast, and mammalian cells. Our results remove a billion-year constraint imposed by the genetic code on the ability to chemically manipulate the structures of proteins. At the same time, in collaboration with F.E. Romesberg, Department of Chemistry, we are generating additional base pairs (based on hydrophobic and metal-ligand interactions) that are thermodynamically stable and can be enzymatically incorporated into DNA with high fidelity.

Publications

Chen, S., Zhang, Q, Wu, X., Schultz, P.G., Ding, S. Dedifferentiation of lineage-committed cells by a small molecule. J. Am. Chem. Soc. 126:410, 2004.

Chin, J.W., Cropp, T.A., Anderson, J.C., Mrukherji, M., Zhang, Z., Schultz, P.G. An expanded eukaryotic genetic code. Science 301:964, 2003.

Wu, X., Ding, S., Ding, Q., Gray, N.S., Schultz, P.G. Small molecules that induce cardiomyogenesis in embryonic stem cells. J. Am. Chem. Soc. 126:1590, 2004.

Yin, J., Beuscher, A.E. IV, Andryski, S.E., Stevens, R.C., Schultz, P.G. Structural plasticity and the evolution of antibody affinity and specificity. J. Mol. Biol. 330:651, 2003.

Zhang, Z., Gildersleeve, J., Yang, Y.Y., Xu, R., Loo, J., Uryu, S., Wong, C.H., Schultz, P.G. A new strategy for the synthesis of glycoproteins. Science 303:371, 2004.

Zheng, L., Liu, J., Batalov, S., Ding, S., Schultz, P.G. A genome-wide screen of the NF-κB pathway using an arrayed siRNA expression library. Proc. Natl. Acad. Sci. U. S. A., in press.

 


Peter G. Schultz, Ph.D.
Professor
Scripps Family Chair

Schultz Web Site