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The Skaggs Institute For Chemical Biology
Scientific Report 1999-2000


Biological Chemistry


P.G. Schultz, J.C. Anderson, S. Atwell, M. Berger, Y.T. Chang, L. Chen, A. Deniz, S. Ding, M. Fa, A.E. Faulhaber, J. Gildersleeve, Z. Guo, T. Habicher, B. Herberich, J. Janes, A. Kawamura, J. Liao, S. Licht, C. Loweth, D. Ly, T. Magliery, A. Martin, E. Meggers, A. Ogawa, M. Pastrnak, J. Perl, R. Riedl, F. Romesberg, S. Roy, S. Santoro, N. Segal, J. Semenova, A. Su, L. Supekova, F. Tian, A. Ting, A. Varvak, L. Wang, C. Watanabe, Y. Wu, G. Xia, S. Yao, J. Yin, D. Zhou

The aim of our research is to combine the tools and principles of chemistry with the molecules and processes of living cells to create molecules with new properties and functions that occur neither naturally nor in the test tube. By studying the structure and function of the resulting molecules, new insights can be gained 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, with specificities rivaling or exceeding those of enzymes. Most recently, we focused on in vitro evolution methods that involve the development of novel chemical screens and selections for detecting mutants with enhanced function. The characterization of catalytic antibodies is also providing insights into the mechanisms and evolution of naturally occurring catalytic 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 biomolecular interactions, and RNA viruses. We are generating structure-based libraries of small molecules that are being used in conjunction with novel protein and cellular screens to identify inhibitors of important proteins involved in cellular processes, including differentiation, proliferation, and signaling. X-ray crystallography, biochemical studies, and genomics experiments are being used to characterize the mode of action of these compounds and to study their effects on cellular processes. We are also developing and applying modern genomics and proteomics tools to a variety of important biomedical problems, including aging, angiogenesis, stem cell differentiation, and viral infectivity.

We also developed a general biosynthetic method that makes it possible to site-specifically incorporate unnatural amino acids into proteins. In the past few years, we effectively expanded the genetic code to include more than 80 unnatural amino acids with novel backbone and side-chain structures. We recently applied the method to studies of the catalytic properties, specificity, and stability of a number of proteins.

Currently, we are attempting to engineer a novel organism with orthogonal tRNAs, synthetases, and codons that can uniquely use electrophilic keto, heavy atom-binding, and fluorescent amino acids in its genetic code. This work takes advantage of the power of organic chemistry and biology to manipulate large systems of molecules to generate new cellular functions. In addition, in collaboration with F. Romesberg, the Skaggs Institute, we began a project to generate an orthogonal third base pair that is thermodynamically stable and can be replicated enzymatically with high fidelity.

Finally, we are combining our ability to selectively manipulate the chemical structures of proteins and nucleic acids with single-molecule optical spectroscopy to study the structure and dynamics of individual protein and DNA molecules. This research includes studies of catalysis, DNA recognition, protein folding, and protein synthesis. The results may provide new insights into biomolecular function that cannot be obtained by studying molecular ensembles.

Publications

Deniz, A.A., Dahan, M., Grunwell, J.R., Ha, T., Faulhaber, A.E., Chemla, D.S., Weiss, S., Schultz, P.G. Single-pair fluorescence resonance energy transfer on freely diffusing molecules: Observation of Förster distance dependence and subpopulations. Proc. Natl. Acad. Sci. U. S. A. 96:3670, 1999.

Guo, Z., Zhou, D., Schultz, P.G. Designing small-molecule switches for protein-protein interactions. Science 288:2042, 2000.

Liu, D.R., Schultz, P.G. Generating new molecular function: A lesson from Nature. Angew. Chem. Int. Ed. 38:4000, 1999.

Liu, D.R., Schultz, P.G. Progress toward the evolution of an organism with an expanded genetic code. Proc. Natl. Acad. Sci. U. S. A. 96:4780, 1999.

Ly, D.H., Lockhart, D.J., Lerner, R.A., Schultz, P.G. Mitotic misregulation and human aging. Science 287:2486, 2000.

 

 







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