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Virginia W. Cornish, Ph.D.
Professor of Chemistry
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Research
Summary
Cornish Lab
Our approach to creating novel enzymes is unique in that it strives to be a direct selection for catalysis and yet remain general and applicable to a wide array of reactions. The selection strategy involves two stages: (1) engineering a cell line that is capable of discriminating between the substrate and product of a reaction, and (2) introducing large libraries of >106 proteins into this cell line and identifying the proteins that can convert the substrate to the product-based on their ability to confer a selective advantage to the individual cells. The projects follow three main directions: methodology development, mechanistic studies of the basis for enzyme catalysis, and the generation of proteins that catalyze commercially important, demanding transformations.
The methodology hinges on the construction of a cell line in which transcriptional activation of a gene essential for the survival of a cell is dependent on the product, but not the substrate, of a reaction. For example, in E. coli the dimerization of the DNA-binding protein 1repressor will be modified to be dependent on the small-molecule product. These projects will combine synthetic chemistry with protein design to provide small molecules that can enter the cell and regulate transcription efficiently.
The ability to compare the catalytic efficiencies of large libraries of protein variants will provide a new tool for understanding the basis for enzyme catalysis. Initially, the selection strategy will be applied to P99 cephalosporinase variants not only to test existing theories of catalysis‹such as the role of critical active-site residues‹but also to provide new insights into the basis for the impressive specifications and rate enhancements achieved by enzymes.
The catalysis of chemically difficult transformations remains an important goal in organic chemistry. Natural enzymes carry out a diverse range of reactions, often both enantio-and regio-selectively. Our aim is to use the genetic selection to create synthetically useful protein catalysts for novel transformations.
http://www.columbia.edu/cu/chemistry/fac-bios/cornish/faculty.html
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Selected Publications:
1. S. Goldberg, W. Iannuccilli, T. Nguyen, J. Ju, V.W. Cornish. (2003) Identification of Residues Critical for Catalysis in a Class C b-Lactamase by Combinatorial Scanning Mutagenesis. Protein Science.
12(8):1633-45.
2. A. Forster, Z. Tan, M.N.L. Nalam, H. Lin, H. Qu, V.W. Cornish, S. Blacklow. (2003) Programming Peptidomimetic Syntheses by Translating Genetic Codes Designed de novo. Proc. Natl. Acad. Sci. USA.
100:6353-6357.
3. K. Baker, C. Bleczinski, H. Lin, G. Salazar-Jimenez, D. Sengupta, S. Krane, V.W. Cornish. (2002) Chemical Complementation: A Reaction-Independent, High-Throughput Genetic Assay for Enzyme Catalysis. Proc. Natl. Acad. Sci. USA.
99:16537-16542.
4. E.A. Althoff and V.W. Cornish. (2002) A Bacterial Small-Molecule Three-Hybrid System. Angew. Chem.
14:2433-2436.
5. E.A. Althoff and V.W. Cornish. (2002) Screening and Selection Methods for the Large Scale Analysis of Protein Function. Angew. Chem.
114:4580-4606.
6. H. Lin, W. Abida, R.T. Sauer, and V.W. Cornish. (2000) Dexamethasone-Methotrexate: An Efficient Chemical Inducer of Protein Dimerization in vivo. J. Am. Chem. Soc.
122:4247-4248.
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Honors and Awards
2003 Sloan Foundation Fellowship
2001 Columbia College Young Alumni Achievement Award
2000 Beckman Young Investigator Award
2000 Burroughs-Wellcome Fund New Investigator Award
2000 National Science Foundation Career Award
1999 Camille and Henry Dreyfus New Faculty Award
1999 Columbia College Alumna Achievement Award
11/1996-10/1998 National Science Foundation Post-Doctoral Fellow
8/1995-10/1996 Howard Hughes Medical Institute Graduate Fellowship
1995 Outstanding Graduate Student Instructor Award
8/1994-7/1995 American Chemical Society Division of Organic Chemistry
Graduate Fellowship
8/1991-7/1994 National Science Foundation Predoctoral Fellowship
1993 Outstanding Graduate Student Instructor Award
1990 Phi Beta Kappa
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