Professor, BIO5 Institute
Professor, Molecular and Cellular Biology
Professor, Applied Mathematics - GIDP
Professor, Cancer Biology - GIDP
Professor, Genetics - GIDP
Dr. Montfort has been a member of the University of Arizona Cancer Center for 25 years. His cancer-related research has focused on mechanism in drug binding and on establishing new targets. More recently, they have been developing new methods for drug screening. Targets of past and current interest include thymidylate synthase, thioredoxin, a new transmembrane target called CD47 that regulates nitric oxide signaling and tumor growth, and a variety of kinases. He is pleased now to serve on this grant as Co-Leader of the Therapeutic Development Program.
Dr. Montfort's research broadly concerns the link between protein structure and protein function, including how ligands and drugs bind to their targets and influence activity. One current focus concerns nitric oxide signaling. Their work includes studies on NO binding, transport and signaling regulation, and our approaches span atoms to animals. Among their studies are crystal structures of proteins containing nitrosyl-heme or nitroso-cysteine, transient kinetic measurements, biophysical measurements of transmembrane complexes and functional measurements in live cells, including forward genetics approaches. They seek mechanistic and regulatory details of importance to numerous diseases, including cardiovascular disease, poor wound healing in diabetes, and angiogenesis and tumor growth in cancer.
These studies and the University of Arizona provide an excellent home for cross-disciplinary student training and collaborative studies. Dr. Montfort directs the Biological Chemistry Graduate Program, which brings together chemists, biochemists and medicinal chemists for research at the chemistry/biology interface and is the marquee training program for drug discovery on campus. He has trained over thirty graduate and postdoctoral students from numerous programs, including Biochemistry, Molecular and Cellular Biology, Chemistry, Applied Mathematics and Pharmacology and Toxicology. He has also been intimately involved in establishing collaborative core facilities.
Dr. Montfort established the Macromolecular Crystallography Core facility in 1990 and has continued as faculty director since that time. He is a past member of numerous core facilities and currently serve on the steering committees for the Functional Genomics Facility and the Proteomics Facility.
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. They 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. They are studying the mechanistic details surrounding cGMP and SNO production, and the signaling consequences of their formation.
For reversible Fe-NO chemistry they are studying soluble guanylate cyclase and the nitrophorins, a family of NO transport proteins from blood-sucking insects. Their crystal structures of nitrophorin 4 extend to resolutions beyond 0.9 angstroms, allowing them 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, the group is exploring the molecular details of NO signaling and whole-cell physiology.