Ph.D. 1984, University of Washington
For seeking admission to the Ph.D. program
F.A. Gillfillan Memorial Award lecture - April 30, 2013
OSU Distinguished Professor Award lecture - May 21, 2015
Proteins play central roles in all aspects of biochemistry. In addition to the proteins that serve as enzymes catalyzing the reactions of metabolism, there are, among others, structural proteins, protein hormones, transport proteins, cell surface receptors and proteins involved in the regulation of DNA replication and transcription.
A theme common to all classes of proteins is specific recognition and function through unique structure. To develop a better understanding of the mechanisms involved in the specificity of recognition and catalysis, we need detailed structural information. I am interested in using X-ray crystallography, complemented by protein chemistry, enzymology and theoretical approaches such as molecular dynamics, to obtain this detailed structural information.
The protein structures we are working on are a diverse group. Proteins are chosen with the dual goal that their detailed study will lead to insights relevant for understanding the particular protein and to insights relevant to understanding general principles of protein structure, stability and function. Most projects being worked on are collaborative and current projects include the following: studies of flavoenzymes to investigate how the enzyme:flavin interactions influence the electronic structure of the flavin, and modulate its reactivity (e.g., ferredoxin reductases, glyceraldehyde-phosphate oxidase, and bacterial SsuE); studies to investigate the structural, functional and evolutionary relationships among peroxiredoxins and to probe their role in hydrogen peroxide signaling in eukaryotes; investigation into the mechanism of the iron-dependent enzyme cysteine dioxygenase important for cysteine catabolism and sulfur metabolism in mammals, and studies on the a series of related enzymes that catalyzes carbon-carbon bonds involved in ring closure reactions of 7-carbon phosphosugars.
In addition to these studies we have an ongoing effort to use empirical studies of ultrahigh-resolution protein structures in the protein data bank to discover detailed features of protein structure that have not yet been recognized. In some cases this leads to fundamental shifts in how we understand the most basic characteristics of proteins, such as the planarity (or perhaps non-planarity) of the peptide bond or the common conformational building blocks from which structures are built. A recent accomplishment has been to characterize how protein covalent geometry varies with conformation. The variation is substantial and we have shown that taking it into account in crystallographic refinement protocol and in homology modeling does produce more accurate structures.
Finally, in collaboration with Kay Diederichs, we have revealed problems with conventional measures of data quality used in protein crystallography, and proposed two novel statistics, CC1/2 and CC*, that are much more robust measures of data quality. We further showed that conventional practices resulted much too conservative resolution cutoffs, so that too much weak but still useful data were discarded. Our recommendations are catching on and resulting in better structures. We have reviewed this work in "Assessing and maximizing data quality in macromolecular crystallography" in Curr Opin Struct Biol (2015) 34:60-68.