Research Interests

Overall Areas of Interest: Protein Structure and Function, Enzyme Kinetics and Allosteric Regulation, Protein Folding,
Structural Genomics.

Background:

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.
 

Specific Projects:

We are attempting to understand the roles that such interactions play in regulating the activity of three metabolically important enzymes, glutamate dehydrogenase, malate dehydrogenase, and 3-phosphoglycerate dehydrogenase. In particular understanding the non-covalent interactions in a protein provides information about the dynamic properties of the protein which we think play important roles in both the activity and regulation of these [and many other] enzymes. These studies involve a combination of chemical and site directed mutagenesis approaches combined with functional studies involving initial rate kinetics, ligand binding and regulation. We use limited proteolysis and Hydrogen-Deuterium Exchange techniques in conjunction with mass spectrometry to directly examine dynamic regions of the proteins, and x ray crystallography to look at the overall structural impact of mutations that we make to interrogate the roles of particular amino acid side chains. A particular focus is on using spectroscopic approaches to detect subtle conformational changes in the active sites of these oligomeric proteins. This project involves collaboration with structural biology groups at the Virginia Commonwealth University and the Danforth Plant Science Institute in St Louis to investigate the structural basis of the allosteric regulation of these proteins.

Glutamate Dehydrogenase
 

Malate Dehydrogenase
 

3-Phosphoglycerate Dehydrogenase

Other projects in the laboratory study protein folding of the thiol protease inhibitors including the stefins and cystatins, and proteins associated with polyglutamine neurodegenerative diseases and  study of the mechanism of gp41 mediated entry of HIV into target cells

Getting Involved:

If you are a first or second year student and interested in working in my research group please contact me to make an appointment to discuss various projects.