Modelling human cytochromes P450 involved in drug metabolism from the CYP2C5 crystallographic template.
A historical background to homology modelling of human P450s involved in drug metabolism is outlined, showing that the progress in crystallographic studies of bacterial forms of enzyme and, latterly, determination of a mammalian P450 crystal structure, has enabled the production of increasingly satisfactory models of human P450 enzymes. The methodology for the generation of P450 models by homology with crystallographic template structures is summarized, and recent results of CYP2C5-constructed models of P450s are described. These indicate that selective substrates are able to fit within the putative active sites of each enzyme, where key contacts with complementary amino acid residues are largely consistent with the results of site-directed mutagenesis experiments and metabolic studies. Consequently, the CYP2C5 crystal structure can be regarded at the current paradigm for homology modelling of the drug metabolizing P450s, especially those from the CYP2 family.
Lewis
David F V
DF
School of Biomedical and Life Sciences, University of Surrey, Guildford, UK. d.lewis@surrey.ac.uk
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013255:Steroid 21-Hydroxylase / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity
D003577:Cytochrome P-450 Enzyme System; C065407:CYP2C5 protein, Oryctolagus cuniculus; D000072467:Cytochrome P450 Family 2; D013255:Steroid 21-Hydroxylase