Chris Dealwis, Ph.D.

The Dealwis lab has moved to the Case Western Reserve University

Research Statement

My research focuses on three areas of interest. They are: (1) the structure-function and regulation of yeast ribonucleotide reductase I (Rnr1) by small molecule effectors and its protein inhibitor, the suppressor of Mec I lethality (Sml1), (2) the structure-function of pathogenic amyloid forming proteins, and (3) the investigation of the catalytic mechanism of E. coli dihydrofolate reductase using neutron and ultra-high resolution X-ray diffraction.

We study the structure-function and regulation of the anti-cancer target ribonucleotide reductase I (Rnr1). Ribonucleotide reductase (RNR), converts nucleotides to deoxy nucleotides (dNTPs), the rate-limiting step in de novo DNA synthesis. Control of the dNTP pool is essential; an excess of deoxynucleotides causes mutations, while scarcity can lead to cell death due to improper cell division. In our lab, we have also studied how Rnr1 is regulated by the small protein inhibitor Sml1.  Three of our recent papers describe how Sml1 self-assembles and some of the details of its regulation.

The aggregation of normally soluble proteins into insoluble, unbranching fibrils is the underlying pathology associated with a family of diseases known as the amyloidoses. My lab has been studying proteins involved in two amyloid diseases: Alzheimer’s and the human amyloid disease.

My third research interest involves the use of neutron and ultra-high resolution X-ray diffraction to solve controversial mechanistic questions. The contribution of hydrogen atoms in noncovalent interactions and enzymatic reactions underlies all aspects of biology at the molecular level, yet their “visualization” is quite difficult.  Neutron diffraction  (ND) is well suited to such studies, as it is able to observe hydrogen atoms. ND is coming of age with the advent of the Spallation neutron source (SNC) at ORNL. We are currently working on the elucidation of the catalytic mechanism of the housekeeping enzyme dihydrofolate reductase (DHFR), from E. coli.

Additional information can be found on the Dealwis lab page.

Selected Publications

Brad C. Bennett, Paul Langan, Leighton Coates, Marat Mustyakimov, Benno Schoenborn, Elizabeth E. Howell, and Chris G. Dealwis. (2006), PNAS, 103, 18493-18498. Neutron diffraction studies of Escherichia coli dihydrofolate reductase complexed with methotrexate.

Hai Xu, Catherine Faber, Tomoaki Uchiki, James W. Fairman, Joseph Racca, and Chris Dealwis. (2006), PNAS, 103, 4022-4027. Structures of eukaryotic ribonucleotide reductase I provide insights into dNTP regulation.

Hai Xu, Catherine Faber, Tomoaki Uchiki, Joseph Racca, and Chris Dealwis. (2006), PNAS, 103, 4028-4033. Structures of eukaryotic ribonucleotide reductase I define gemcitabine diphosphate binding and subunit assembly.

Gardberg AS, Tanner N, Huff I, Salone K, Wetzel R, Dealwis C. Modeling studies of anti-amyloid antibodies bound to Aβ. Etter Transactions Volume 1: 15-28 2005.

Brad C. Bennett, Flora Meilleur, Dean A.A. Myles, Elizabeth E. Howell, and Chris G. Dealwis. (2005), Acta Cryst. D61, 574-9. Preliminary Neutron Diffraction Studies of E. coli Dihydrofolate Reductase Bound to the Anticancer Drug Methotrexate.

Joshua S. Sharp, Jun-tao Guo, Tomoaki Uchiki, Ying Xu,Chris Dealwis , Robert L. Hettich. (2005) J. Anal. Biochem, 340, 201-212, Photochemical surface mapping of C14S-Sml1p for constrained computational modeling of protein structure.

Dealwis, C., and Wall, J. (2004). J. Curr. Drug. Tar. 5, 159-71, Towards understanding the structure-function relationship of human amyloid disease.

Gupta, V., Peterson, C. B., Dice, L. T., Uchiki, T., Racca, J., Guo, J. T., Xu, Y., Hettich, R., Zhao,X., Rothstein, R. and Dealwis, C. G. (2004), Biochemistry, 43, 8568-8578. Sml1p Is a Dimer in Solution: Characterization of Denaturation and Renaturation of Recombinant Sml1.

Uchiki, T., Dice, L. T., Hettich, R. L. and Dealwis, C. (2004), J. Biol. Chem.  279, 11293-303. Identification of phosphorylation sites on the yeast ribonucleotide reductase inhibitor Sml1.

Wall, J, S., Gupta, V., Wilkerson, M., Schell, M., Loris, R., Adams, P., Solomon, A., Stevens, F., and Dealwis, C., (2004), J. Mol. Recog., Structural basis of light chain amyloidogenecity: comparison of the thermodynamic properties, fibrillogenic potential and tertiary structure features of four Vλ6 proteins.

Uchiki, T.,  Hettich, R., Gupta, V and Dealwis, C. (2002), J. Anal. Biochem. 301, 35-48 structural characterization of recombinant SML1P-HISTAG protein monomer and dimer by electrospray FTICR-MS.

Dealwis, C., Fernandez, E. J., Thompson, D. A., Siani, M., and Lolis, E. (1998)   PNAS, 95,12,6941-6 Crystal Structure of Chemically Synthesized [N33A] SDF-1a a Potent Ligand for the HIV-1 "Fusin" Co-Receptor

Contact Information

Office:
Room F-433
Walters Life Sciences
Phone: (865) 974-4088

Lab:
Room E-414
Walters Life Sciences
Phone: (865) 974-3047

Email:cdealwis@utk.edu