Using x-ray diffraction data collected at SSRL, Scripps researchers Jason Yano, Eric F. Johnson, C. David Stout, and their colleagues have solved the structure of a type of human P450 enzyme called CYP2A6, which is the principal enzyme in the body that degrades nicotine.

CYP2A6 is a protein that can be found in liver cells, where it is one of many enzymes responsible for removing toxic chemicals from the body. In the case of nicotine, however, CYP2A6 is responsible for breaking down approximately 80% of the chemical in the bloodstream as it circulates through the liver. With that in mind, the research team set out to solve the structure of the CYP2A6 protein with two different inhibitors (coumarin and methoxsalen) bound to it. Because they are membrane-bound proteins, this class of enzymes has been particularly difficult to work with. As a workaround, the researchers "clipped off" the end of the molecule that sits in the membrane, concentrating instead on the end of CYP2A6 that contains the iron-containing active site, the P450 heme moiety.

Their studies have revealed in fine detail the exact active site structure of the enzyme. This structural information is being used in ongoing high-resolution macromolecular crystallography experiments at SSRL to probe the active site of this P450 2A6 with additional small molecule compounds. These studies may ultimately lead to the design of an effective inhibitor of P450 2A6 that could be used to decrease the occurrence of smoking and tobacco-related cancers by reducing dependence on nicotine and by blocking formation of carcinogens.

Yano, J.K., Hsu, M.-H., Griffin, K.J., Stout, C.D. and Johnson, E.F. (2005) The structure of human microsomal cytochrome P450 2A6 with coumarin and methoxsalen bound. Nature Struct. Mol. Biol. 12, 822-823.