William Montfort received BS and PhD degrees in Chemistry (Biochemistry emphasis) from Oakland University (1980) and the University of Texas (1985). His graduate studies, with Prof. Jon Robertus, led to the crystal structure of ricin. In his postdoctoral studies, with Prof. Robert Stroud at the University of California, San Francisco, he determined crystal structures of anticancer drug target thymidylate synthase. He moved to the University of Arizona in 1989, where he established a laboratory focused on protein structure/function and founded the X-ray crystallography facility. He is now Professor of Chemistry and Biochemistry, and Director of the NIH-funded Biological Chemistry Graduate Program.
- Biophysics
- Metabolism
- Signaling
- Regulation
- Protein and Membrane Biochemistry
- Structural Biology
Dr. Montfort's group determines the atomic structures of proteins and seeks to understand how protein structure gives rise to protein function – both in vitro and in living cells. The problems they study have at their heart a fundamental structure-function question, but also address questions of importance to human health. Their approaches include X-ray crystallography, rapid kinetic measurements, spectroscopy, theory, protein expression, drug discovery, molecular genetics and related techniques.
They are particularly interested in nitric oxide signaling mechanisms. Nitric oxide (NO) is a small reactive molecule produced by all higher organisms for the regulation of an immensely varied physiology, including blood pressure regulation, memory formation, tissue development and programmed cell death. The group is interested in two NO signaling mechanisms: binding of NO to heme and the nitrosylation (nitrosation) of cysteines. NO, produced by NO synthase, binds to soluble guanylate cyclase (sGC) at a ferrous heme center, either in the same cell or in nearby cells. Binding leads to conformational changes in heme and protein, and to induction of the protein’s catalytic function and the production cGMP. NO can also react with cysteine residues in proteins, giving rise to S-nitroso (SNO) groups that can alter protein function. They are studying the mechanistic details surrounding cGMP and SNO production, and the signaling consequences of their formation.
For reversible Fe-NO chemistry we are studying soluble guanylate cyclase and the nitrophorins, a family of NO transport proteins from blood-sucking insects. The group's crystal structures of nitrophorin 4 extend to resolutions beyond 0.9 angstroms, allowing us to view hydrogens, multiple residue conformations and subtle changes in heme deformation. For reversible SNO chemistry, they are studying thioredoxin, glutathione S-nitroso reductase (GSNOR) and also sGC. For regulation in the cell, they have constructed a model cell system based on a human fibrosarcoma called HT-1080, where sGC, NO synthase, thioredoxin and GSNOR can be manipulated in a functional cellular environment. With these tools, they are exploring the molecular details of NO signaling and whole-cell physiology.