The main objective of the proposed research is to determine the structure of a 16.7 kDa membrane-associated cytochrome-b5, an electron transfer protein found in a variety of cell types. It plays a major role in the catalytic activity of cytochrome-P450, which metabolizes more than 50% of the drugs in clinical use today. It is also involved as an electron transfer component in a number of oxidative reactions in biological tissues, which includes the anabolic metabolism of fats and steroids. It presents significant challenges for experimental techniques of protein structure determination. However, structure determination of membrane proteins by NMR spectroscopy is in a rapid phase of development;recent results on several membrane proteins are promising and indicate that the structure determination of cytochrome-b5 is feasible. The structure of cytochrome-b5 will be determined in micelles by solution NMR and in lipid bilayers by solid state NMR techniques. Structures obtained in free and in complexation with cytochrome-P450 will provide insights into the molecular mechanism by which cytochrome-b5 influences the catalysis of cytochrome-P450.
The outcome of the proposed structural studies on cytochrome-b5 will provide insights into molecular mechanism by which cytochrome-b5 influences oxidation by cytochrome- P450 that metabolizes more than 50% of current-day drugs. These studies will also enable us to understand the role of cytochrome-b5 in the biosynthesis of testosterone and numerous unsaturated lipids, which are necessary for maintaining the integrity of cellular membranes.
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