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| Dean Wilcox received his BS and MS degrees in Chemistry from the University of California at Riverside. He then pursued graduate research at MIT and Stanford University, studying the electronic structure and chemistry of dinuclear Cu sites in proteins, enzymes and model complexes. After obtaining his PhD in Inorganic Chemistry from MIT in 1984, Dr. Wilcox joined the faculty of Dartmouth College. |
Position: Professor of Chemistry
E-Mail: Dean E. Wilcox
Our research lies at the interface of inorganic chemistry and biochemistry, and is directed toward understanding the interaction of metal ions with proteins and other biological molecules. The overall goal of these studies is to determine the chemical basis (binding, reactions, structural effects) for the biological roles and physiological effects of metal ions. Much of our current research focuses on the coordination chemistry of proteins and peptides that are rich in cysteine (Cys) or histidine (His) amino acids, which are potential ligands for metal ions. Our approach involves quantifying metal ion binding to a protein or selected peptide sequence, and then using spectroscopic and physical methods to characterize the resulting metal-protein/peptide complex. An important component of these studies involves isothermal titration calorimetry (ITC) to analyse the thermodynamics of metal binding (1).
A number of proteins involved in metal transport contain amino acid sequences that are rich in histidines. Since His is an excellent ligand for Cu(II), Ni(II), and other metal ions, we have begun to quantify the metal-binding stoichiometry and affinity of these His-rich sequences to understand metal ion selectivity by these proteins. One example we are studying is the unique peptide sequence, -PHGHGHGHGP- (P=proline, H=histidine, G=glycine), found in an intracellular loop of IRT1, a transmembrane Fe-transporting protein identified in Arabidopsis thaliana by Prof. Mary Lou Guerinot of the Dartmouth Biology Department (2). Another example we are studying is Hpn (3), a unique small protein from Helicobacter pylorithat has 28 histidines among its 60 residues and may play a role in Ni metabolism in this microorganism.
We are also interested in the coordination chemistry of cysteine, which has a preference for “soft” metal ions and can also be oxidized. We have studied (4) the unique small Cys-rich protein metallothionein (MT), which has 20 cysteines among its 61 residues and binds 7-12 metal ions in response to toxic levels of the metal. More recently we have studied the coordination chemistry of so-called zinc fingers that bind Zn(II) with four cysteines and histidines (5). This research is now part of the Dartmouth Superfund Basic Research Program, where the focus is toxic metal interactions with cellular proteins (6). The goals here are to quantify the binding of As, Ni, Cr and other toxic metals to certain target proteins (transcription factors, enzymes, DNA repair proteins), characterize metal-induced changes in the structure and function of the protein, and determine the products of metal-protein reactions (7), which may be useful as molecular “biomarkers” of toxic metal exposure.
We have a long standing interest in metalloenzymes that use two metal ions (8) and have studied the binuclear nickel enzyme, urease, which catalyses the hydrolysis of urea to ammonia and carbon dioxide. Our earlier SQUID magnetic measurements (9) showed a weak magnetic interaction between the two Ni(II) ions and indicated a bridging ligand (10), which was later confirmed by X-ray crystallography (11). Many of our studies have involved competitive inhibitors and spectroscopic methods to characterize the role of the Ni(II) ions in the hydrolysis reaction at the urease active site. Recently we have renewed an earlier interest in the binuclear copper enzyme tyrosinase (12), which catalyses the o-hydroxylation of phenols and their subsequent oxidation to the o-quinone.
Another research area focuses on the bioinorganic chemistry of nitric oxide (NO), considering both its interaction with hemoglobin (13), cobalamin (14) and other biological molecules, and its possible role(s) in neurodegenerative diseases. A major goal of this research is the development and application of methods to quantify NO in living organisms, primarily by trapping NO with metal complexes and using EPR spectroscopy to detect the resulting metal-nitrosyl species (15).
