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Papers In Press, published online ahead of print December 13, 2005
Discovery Research, GlaxoSmithKline, Harlow, Essex CM19 5AW
Corresponding Author: Paul_2_Rowland{at}gsk.com
Cytochrome P450 2D6 is a heme containing enzyme which is responsible for the metabolism of at least 20% of known drugs. Substrates of 2D6 typically contain a basic nitrogen and a planar aromatic ring. The crystal structure of human 2D6 has been solved and refined to 3.0 Å resolution. The structure shows the characteristic P450 fold as seen in other members of the family, with the lengths and orientations of the individual secondary structural elements being very similar to those seen in 2C9. There are however several important differences, the most notable involving the F helix, the F-G loop, the B’ helix, beta sheet 4 and part of beta sheet 1, all of which are situated on the distal face of the protein. The 2D6 structure has a well defined active site cavity above the heme group, containing many important residues which have been implicated in substrate recognition and binding, including Asp-301, Glu-216, Phe-483 and Phe-120. The crystal structure helps to explain how Asp-301, Glu-216 and Phe-483 can act as substrate binding residues, and suggests the role of Phe-120 is to control the orientation of the aromatic ring found in most substrates with respect to the heme. The structure has been compared to published homology models and has been used to explain much of the reported site directed mutagenesis data and help understand the metabolism of several compounds.
J. Biol. Chem, 10.1074/jbc.M511232200
Submitted on October 16, 2005
Revised on November 22, 2005
Accepted on December 13, 2005
Crystal structure of human cytochrome P450 2D6
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