Donald Voet

We are studying the structures of biologically interesting molecules by X-ray crystallography in an effort to understand their structure-function relationships. Current projects include:

Yeast inorganic pyrophosphatase

Pyrophosphatases are essential enzymes that catalyze the hydrolysis of inorganic pyrophosphate to phosphate and, in doing so, drive the many biosynthetic reactions that yield pyrophosphate (e.g., polypeptide and polynucleotide synthesis) to completion. We have determined the refined 2.7-angstrom resolution structure of yeast inorganic pyrophosphatase, a dimeric enzyme of identical 286-residue subunits. We are presently determining the X-ray structures of selected mutant forms of this enzyme, both alone and in complex with inhibitors of this enzyme. The results of these studies, when correlated with the enzymological characteristics of the mutant enzymes, should lead to the formulation of a catalytic mechanism of inorganic pyrophosphatases as well as a greater understanding of biological phosphoryl transfer reactions in general.

Granulocyte -macrophage colony-stimulating factor (GM-CSF)

GM-CSF is a protein growth factor (cytokine) that stimulate the differentiation, proliferation, and activation of white blood cells known as granulocytes and macrophages. The therapeutic use of GM-CSF therefore holds considerable promise for the treatment of immunosuppressive conditions such as AIDS and the consequences of cancer chemotherapy. Indeed, GM-CSF is presently in clinical use to facilitate bone marrow transplantation. We have determined the refined X-ray structure of human GM-CSF to 3.0-angstrom resolution. We plan to determine the X-ray structures of selected mutant varieties of human GM-CSF in an effort to understand how GM-CSF interacts with its cell surface receptor. We also intend to determine the X-ray structure of the human GM-CSF receptor, both alone and in complex with GM-CSF. 

The x-ray structure of yeast inorganic pyrophosphatase. A 286-residue monomer unit of this homodimeric enzyme is shown with its polypeptide backbone represented in ribbon form embedded in its solvent accessible surface. The side chains of its active site residues are shown in ball-and-stick form.