Professor
Floyd D. and Elisabeth S. Gottwald Chair in Chemistry
Biochemistry
office: Gottwald Center for the Sciences, D303
phone: 804-289-8244
email: jbell2@richmond.edu
homepage: http://facultystaff.richmond.edu/~jbell2
Education:
Ph.D. - Oxford University
Classes Taught: (Fall 2008)
CHEM112 – Biochemistry in the Real World
CHEM112-L01 – Biochemistry in the Real World Lab
Research Interests:
Covalent structure of biologically active molecules such as proteins and enzymes is readily available from enterprises such as the human genome project. This information however represents only the first stage of an intriguing series of questions relating to protein structure-function relationships that requires a detailed understanding of the non-covalent interactions in proteins and how subtle changes in covalent structure, such as produced by phosphorylation or glycosylation can dramatically change biological function.
The research of my group focuses on understanding the roles that non-covalent interactions play in four different biologically important systems.
Specific Projects:
In the first we are attempting to understand the roles that such interactions play in regulating the activity of four metabolically important enzymes, glutamate dehydrogenase, malate dehydrogenase, 3-phosphoglycerate dehydrogenase and fumarase. These studies involve a combination of chemical and site directed mutagenesis approaches combined with functional studies involving initial rate kinetics, ligand binding and regulation. A particular focus is on using spectroscopic approaches to detect subtle conformational changes in the active sites of these oligomeric proteins. We use both direct experimentation and computational chemistry approaches to relate structure to function both at the level of fundamental events in the catalytic cycle of these enzymes and in the regulation of the activity by subunit interactions. This project involves collaborations with the structural biology groups at Washington University, St Louis, University of Minnesota, UC Berkeley, and University of California at San Francisco to investigate the structural basis of the allosteric regulation of these proteins.
In the second project we are investigating the folding of the thiol protease inhibitor cystatin and potential mis-folding events giving beta sheet aggregates. By elucidating the non-covalent interactions that trigger the folding of this relatively small protein we hope to understand how a unique phosphorylation we discovered several years ago plays a role in regulating the activity of this ubiquitous protein. Folding of the protein is characterized by spectroscopic means [CD, Fluorescence and NMR] as well as by activity measurements. In addition, we are probing by a variety of site directed mutagenesis and chemical probes the interaction with target proteases to understand how structural alterations in cystatin may regulate protease specificity. This project has a number of biotechnological applications including the construction of transgenic plants and the engineering of chicken cystatin to mimic human salivary cystatin, which we are actively pursuing.
The third project involves both structural genomic and biophysical approaches to investigate two virally encoded proteins from cytomegalovirus. The first protein, which our previous work suggests is a new class of protein kinase has homologs in several other herpes family members. The second protein is apparently related to the histocompatibility antigens of normal cells. Neither protein has been previously isolated or characterized. The overall goal of this project is to characterize these proteins by a variety of structural and enzymological approaches. In the long run we hope to identify the cellular targets of the kinase in infected cells to elucidate the role of this protein in the infection process.
The final project brings together several of our overall interests in phosphorylation, physical interactions and protein function. We are investigating the interaction between various proteins [including cystatin] and mineralized surfaces. A current focus of this work is investigating the potential formation of soft tissue-hard tissue interfaces such as the cartilage-bone interface. This work involves chondrocyte cell culture and biochemical probes of cell differentiation in conjunction with biophysical probes of tissue mineralization including X ray diffraction and Scanning Electron Microscopy.