In the past, we have exploited the natural genetic diversity of the humoral immune system to make highly selective catalysts, to test fundamental notions of biological catalysis, and to analyze the molecular basis for germline polyspecificity and affinity maturation. Here we propose to extend these efforts to the generation of antibodies with engineered metal binding sites. These studies will likely facilitate both chemical and therapeutic applications of antibodies. In addition, we will pursue two additional efforts that have evolved from work in antibody catalysis. The first focuses on the evolution of novel protein structures and functions by the combinatorial association and subsequent mutation of bacterial secondary structural elements. The second focuses on novel redox activities associated with membrane bound receptors?specifically human growth factor and related receptors. These latter projects will provide new insights into the evolution of protein structure and function, and the role of redox processes in biological recognition and cell signaling, respectively.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Jones, Warren
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Scripps Research Institute
La Jolla
United States
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Mills, Jeremy H; Lee, Hyun Soo; Liu, Chang C et al. (2009) A genetically encoded direct sensor of antibody-antigen interactions. Chembiochem 10:2162-4
Graziano, James J; Liu, Wenshe; Perera, Roshan et al. (2008) Selecting folded proteins from a library of secondary structural elements. J Am Chem Soc 130:176-85
Debler, Erik W; Kaufmann, Gunnar F; Meijler, Michael M et al. (2008) Deeply inverted electron-hole recombination in a luminescent antibody-stilbene complex. Science 319:1232-5
Tian, Feng; Debler, Erik W; Millar, David P et al. (2006) The effects of antibodies on stilbene excited-state energetics. Angew Chem Int Ed Engl 45:7763-5
Tian, Feng; Tsao, Meng-Lin; Schultz, Peter G (2004) A phage display system with unnatural amino acids. J Am Chem Soc 126:15962-3
Yin, Jun; Mills, Jeremy H; Schultz, Peter G (2004) A catalysis-based selection for peroxidase antibodies with increased activity. J Am Chem Soc 126:3006-7
Venkateshrao, Swarnalatha; Yin, Jun; Jarzecki, Andrzej A et al. (2004) Porphyrin distortion during affinity maturation of a ferrochelatase antibody, monitored by Resonance Raman spectroscopy. J Am Chem Soc 126:16361-7
Yin, Jun; Beuscher 4th, Albert E; Andryski, Scott E et al. (2003) Structural plasticity and the evolution of antibody affinity and specificity. J Mol Biol 330:651-6
Yin, Jun; Andryski, Scott E; Beuscher 4th, Albert E et al. (2003) Structural evidence for substrate strain in antibody catalysis. Proc Natl Acad Sci U S A 100:856-61
Gildersleeve, Jeff; Varvak, Alex; Atwell, Shane et al. (2003) Development of a high-throughput screen for protein catalysts: application to the directed evolution of antibody aldolases. Angew Chem Int Ed Engl 42:5971-3

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