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William R. MontfortProfessor of Biochemistry and Molecular Biophysics Professor of Chemistry Professor, BIO5 Institute for Collaborative Research montfort@email.arizona.edu BioSciences West 533 Phone: (520) 621-1884 Fax: (520) 621-1697 |
Honors
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Education and Appointments
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Research Interests
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Research Summary | |
| Protein Structure, Function and Inhibition My 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 we study have at their heart a fundamental structure-function question, but also address questions of importance to human health. Our approaches include X-ray crystallography, rapid kinetic measurements, spectroscopy, theory, protein expression, drug discovery, molecular genetics and related techniques. We 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. We are 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. We 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. Our 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, we are studying thioredoxin, glutathione S-nitroso reductase (GSNOR) and also sGC. For regulation in the cell, we 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, we are exploring the molecular details of NO signaling and whole-cell physiology. | |
Selected Publications | |
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