A 3-DIMENSIONAL PROTEIN MODEL FOR HUMAN CYTOCHROME-P450 2D6 BASED ON THE CRYSTAL-STRUCTURES OF P450-101, P450-102, AND P450-108

Cytochromes P450 (P450s) constitute a superfamily of phase I enzymes c apable of oxidizing and reducing various substrates. P450 2D6 is a pol ymorphic enzyme, which is absent in 5-9% of the Caucasian population a s a result of a recessive inheritance of gene mutations. This deficien cy leads to impaired metabolism of a variety of drugs. All drugs metab olized by P450 2D6 contain a basic nitrogen atom, and a flat hydrophob ic region coplanar to the oxidation site which is either 5 or 7 Angstr om away from the basic nitrogen atom. The aim of this study was to bui ld a three-dimensional structure for the protein and more specifically for the active site of P450 2D6 in order to determine the amino acid residues possibly responsible for binding and/or catalytic activity. F urthermore, the structural features of the active site can be implemen ted into the existing small molecule substrate model, thus enhancing i ts predictive value with respect to possible metabolism by P450 2D6. A s no crystal structures are yet available for membrane-bound P450s (su ch as P450 2D6), the crystal structures of bacterial (soluble) P450 10 1 (P450(cam)), P450 102 (P450(BM3)), and P450 108 (P450(terp)) have be en used to build a three-dimensional model for P450 2D6 with molecular modeling techniques. Several important P450 2D6 substrates were conse cutively docked into the active site of the protein model. The energy optimized positions of the substrates in the protein agreed well with the original relative positions of the substrates within the substrate model. This confirms the usefulness of small molecule models in the a bsence of structural protein data. Furthermore, the derived protein mo del indicates new leads for experimental validation and extension of t he substrate model.