A three-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 capable of oxidizing and reducing various substrates. P450 2D6 is a polymorphic enzyme, which is absent in 5-9% of the Caucasian population as a result of a recessive inheritance of gene mutations. This deficiency leads to impaired metabolism of a variety of drugs. All drugs metabolized by P450 2D6 contain a basic nitrogen atom, and a flat hydrophobic region coplanar to the oxidation site which is either 5 or 7 A away from the basic nitrogen atom. The aim of this study was to build 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. Furthermore, the structural features of the active site can be implemented into the existing small molecule substrate model, thus enhancing its predictive value with respect to possible metabolism by P450 2D6. As no crystal structures are yet available for membrane-bound P450s (such as P450 2D6), the crystal structures of bacterial (soluble) P450 101 (P450cam), P450 102 (P450BM3), and P450 108 (P450terp) have been used to build a three-dimensional model for P450 2D6 with molecular modeling techniques. Several important P450 2D6 substrates were consecutively 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 absence of structural protein data. Furthermore, the derived protein model indicates new leads for experimental validation and extension of the substrate model.
Leiden/Amsterdam Center for Drug Research (LACDR), Division of Molecular Toxicology, The Netherlands.
M J
MJ
de Groot
N P
NP
Vermeulen
J D
JD
Kramer
F A
FA
van Acker
G M
GM
Donné-Op den Kelder
D000595:Amino Acid Sequence; D001426:Bacterial Proteins; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry*; D003647:Debrisoquin / Q000494:pharmacology; D006801:Humans; D006899:Mixed Function Oxygenases / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009251:NADPH-Ferrihemoprotein Reductase; D010879:Piperazines / Q000494:pharmacology; D017433:Protein Structure, Secondary; D046948:Secologanin Tryptamine Alkaloids; D016415:Sequence Alignment; D013379:Substrate Specificity; D015016:Yohimbine / Q000031:analogs & derivatives / Q000494:pharmacology
D001426:Bacterial Proteins; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D010879:Piperazines; D046948:Secologanin Tryptamine Alkaloids; D015016:Yohimbine; C005709:raubasine; D003577:Cytochrome P-450 Enzyme System; C043425:vanoxerine; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D009251:NADPH-Ferrihemoprotein Reductase; C052423:flavocytochrome P450 BM3 monoxygenases; D003647:Debrisoquin