Mitchell Lewis, D. Phil.

faculty photo
John Morgan Professor of Biomedical Research and Education
Department: Biochemistry and Biophysics
Graduate Group Affiliations

Contact information
813B Stellar-Chance Laboratories
422 Curie Blvd.
Philadelphia, PA 19104
Office: (215) 898-0949
D.Phil. (Biophysics)
Oxford University, 1980.
Permanent link
> Perelman School of Medicine   > Faculty   > Details

Description of Research Expertise

The major objective of our research is to understand how proteins respond to metabolites and regulate transcription. Our work has focused on the repressor of bacteriophage lambda and the lac operon of E. coli. For almost half a century, these two systems have served as the paradigm for understanding gene regulation. The primary focus of our lab has been to provide detailed structural information on these two systems.

The key component of the operon is the lac repressor. The lac operon provides one of the best models for understanding how a set of structural genes may be switched on or off depending upon the concentration of metabolites. We determined the three-dimensional structures of the intact lac repressor, the lac repressor bound to the gratuitous inducer 1-isopropyl-b-D-thiogalactoside (IPTG) and the lac repressor complexed with a 21 base-pair symmetric operator DNA. (Lewis et al., 1996). The continuing overall goal of this work is to build on the biochemical, genetic, and structural data to obtain a more detailed understanding of the specificity of repressor binding and the structural basis for the allosteric response.

Interactions between transcription factors, bound to separate operator sites, commonly play an important role in gene regulation by mediating cooperative binding to the DNA. However, few detailed structural models for understanding the molecular basis of such cooperativity are available. The cI repressor of bacteriophage l is a classic example of a protein that binds to its operator sites cooperatively. The C-terminal domain of the repressor mediates dimerization, as well as a dimer-dimer interaction that results in the cooperative binding of two repressor dimers to adjacent operator sites. We have determined the structure of the l repressor C-terminal domain and identified the interactions that mediate cooperativity. Using the structure, genetics and biochemical data, we have determined the cooperative binding of two l repressor dimers at adjacent operator sites.

Selected Publications

Bell, C.E., P. Frescura, A. Hichchild and M. Lewis: Crystal structure of a C-terminal domain of lambda repressor. Cell 01: 801-11, 2001.

Bell, C.E., Matthews, K.S and Lewis, M.: Crystal structure of the K84L mutant dimeric lac repressor at 1.6A resolution: a thermostable protein JMolBio 2001.

Yi, Jin, Stayrook, S.E., Albert,R.H., Palackal, N.T., Penning, T.M., Lewis,M.: Crystal Structure of Human Type III 3a-Hyroxysteroid Dehydrogenase/ Bile Acid Binding Proteiin Complexed with NADP+ and Ursodeoxycholate. Biochemistry 4(34): 10161-68, 2001.

Bell, C.E., and M. Lewis: Crystal structure of a dimeric lac repressor bound to operatotr at 2.6A resolution: a closer view of the allosteric transition. Nature Struc. Biol. 3: 209-14, 2000.

Summa, C.M., A. Lombardi, M. Lewis and D.F. DeGrado: Tertiary templates for the design of diiron proteins. Current Opinion in Structural Biology 6: 500-505, 1999.

back to top
Last updated: 12/16/2014
The Trustees of the University of Pennsylvania