Burstyn Group

               Bioinorganic Chemistry at the University of Wisconsin

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Soluble guanylyl cyclase
Nitric oxide is a versatile intercellular signaling molecule with a critical role in controlling blood pressure through its receptor soluble guanylyl cyclase (sGC). This enzyme is a key target for NO in humans, responding to the NO signal by producing cGMP. The historic importance for NO-releasing drugs such as nitroglycerine and sodium nitroprusside, and the recent discovery of the drugs Viagra and Cialis, demonstrate the therapeutic potential of modulating the NO/cGMP pathway. The sGC protein is an obvious potential target for new drugs to control blood flow; however, little is known about how sGC functions. The goal of our research is to elucidate the mechanisms by which sGC is regulated, thereby enhancing our understanding of cGMP generation and opening new avenues for drug therapy. NO regulates sGC activity by binding to a heme moiety in the enzyme, and displacing a histidine ligand from the heme. The ligand displacement is hypothesized to cause a conformational change in the protein that results in a dramatic increase in enzyme activity. We are working to understand how this change takes place using spectroscopic and enzymological methods to probe the structure and function of the enzyme. Our specific goals are: 1) to understand how changes at the heme site upon NO binding trigger the activation of sGC; 2) to understand how changes at the active site result in increased activity; and 3) to understand how the two sites are coupled to one another through changes in protein conformation.

 

There is no crystal structure of sGC. The enzyme exists as a heterodimer with a catalytic and heme-binding domain at the subunit interface. Based on the primary sequence, the two functional domains are at opposite ends of the enzyme, although protein folding may put them spatially much closer. Characterization of the heme domain is accomplished primarily via spectroscopic methods including electronic absorption and resonance Raman.