Chris Dealwis Assistant Professor, Department of Biochemistry, Cellular and Molecular Biology The University of Tennessee PhD: University of London, UK F433 Walters Life Sciences 1414 W. Cumberland Ave Knoxville, TN 37996 865-974-4088 cdealwis@utk.edu

Keywords:
Crystallography and Neutron scattering

Research Area:
Structure-function study of Signal Transduction pathways. Knowledge-based drug design

Description of Research:
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.

Selected Publications:

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


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


• Wall, JS, Gupta V, Wilkerson M, Schell M, Loris R, Adams P, Solomon A, Stevens F and Dealwis C (2004) Structural basis of light chain amyloidogenicity: comparison of the thermodynamic properties, fibrillogenic potential and tertiary structural features of four Vlambda6 proteins. J. Mol. Recognit. 17: 323-31.


• Dealwis C, and Wall J (2004) Towards understanding the structure-function relationship of human amyloid disease Curr. Drug Targets 5: 159-71. Uchiki T, Hettich R, Gupta V and Dealwis C (2002) Characterization of monomeric and dimeric forms of recombinant Sml1p-histag protein by electrospray mass spectrometry. Anal. Biochem. 301: 35-48.


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


• Dealwis, CG, Brennan C, Christianson K, Mandecki W and Abad-Zapatero C (1995) Crystallographic Analysis of Reversible Metal Binding Observed in a Mutant (Asp153->Gly) of E. coli Alkaline Phosphatase. Biochemistry 34: 43 13967-73.


• Dhanaraj V1, Dealwis1 CG, Frazao C, Badasso M, Sibanda BL, Tickle IJ, Cooper JB, Driessen HPC, Newman M, Aguilar C, Wood SP, Blundell TL, Hobart P, Geoghegan KF, Ammirati MJ, Danley DE, O'Connor BA and Hoover DJ (1992) X-ray analysis of peptide-inhibitor complexes define the structural basis of specificity for human and mouse renin. Nature 357: 466-471. (V.D. and C.G.D. are joint first authors)